Compositions and methods for the diagnosis and treatment of tumor

ABSTRACT

The present invention is directed to compositions of matter useful for the diagnosis and treatment of tumor in mammals and to methods of using those compositions of matter for the same.

RELATED APPLICATIONS

[0001] This application is a continuation of U.S. patent applicationSer. No. 10/241,220, filed Sep. 11, 2002, which claims priority to U.S.Provisional Patent Application Nos. 60/323,268, filed Sep. 18, 2001,60/339,227, filed Oct. 19, 2001, 60/336,827, filed Nov. 7, 2001,60/331,906, filed Nov. 20,2001, 60/345,444, filed Jan. 2, 2002,60/369,724, filed Apr. 3, 2002 and 60/404,809, filed Aug. 19, 2002, theentirety of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention is directed to compositions of matteruseful for the diagnosis and treatment of tumor in mammals and tomethods of using those compositions of matter for the same.

BACKGROUND OF THE INVENTION

[0003] Malignant tumors (cancers) are the second leading cause of deathin the United States, after heart disease (Boring et al., CA Cancel J.Clin. 43:7(1993)). Cancer is characterized by the increase in the numberof abnormal, or neoplastic, cells derived from a normal tissue whichproliferate to form a tumor mass, the invasion of adjacent tissues bythese neoplastic tumor cells, and the generation of malignant cellswhich eventually spread via the blood or lymphatic system to regionallymph nodes and to distant sites via a process called metastasis. In acancerous state, a cell proliferates under conditions in which normalcells would not grow. Cancer manifests itself in a wide variety offorms, characterized by different degrees of invasiveness andaggressiveness.

[0004] In attempts to discover effective cellular targets for cancerdiagnosis and therapy, researchers have sought to identify transmembraneor otherwise membrane-associated polypeptides that are specificallyexpressed on the surface of one or more particular type(s) of cancercell as compared to on one or more normal non-cancerous cell(s). Often,such membrane-associated polypeptides are more abundantly expressed onthe surface of the cancer cells as compared to on the surface of thenon-cancerous cells. The identification of such tumor-associated cellsurface antigen polypeptides has given rise to the ability tospecifically target cancer cells for destruction via antibody-basedtherapies. In this regard, it is noted that antibody-based therapy hasproved very effective in the treatment of certain cancers. For example,HERCEPTIN® and RITUXAN® (both from Genentech Inc., South San Francisco,Calif.) are antibodies that have been used successfully to treat breastcancer and non-Hodgkin's lymphoma, respectively. More specifically,HERCEPTIN® is a recombinant DNA-derived humanized monoclonal antibodythat selectively binds to the extracellular domain of the humanepidermal growth factor receptor 2 (HER2) proto-oncogene. HER2 proteinoverexpression is observed in 25-30% of primary breast cancers. RITUXAN®is a genetically engineered chimeric murine/human monoclonal antibodydirected against the CD20 antigen found on the surface of normal andmalignant B lymphocytes. Both these antibodies are recombinantlyproduced in CHO cells.

[0005] In other attempts to discover effective cellular targets forcancer diagnosis and therapy, researchers have sought to identify (1)non-membrane-associated polypeptides that are specifically produced byone or more particular type(s) of cancer cell(s) as compared to by oneor more particular type(s) of non-cancerous normal cell(s), (2)polypeptides that are produced by cancer cells at an expression levelthat is significantly higher than that of one or more normalnon-cancerous cell(s), or (3) polypeptides whose expression isspecifically limited to only a single (or very limited number ofdifferent) tissue type(s) in both the cancerous and non-cancerous state(e.g., normal prostate and prostate tumor tissue). Such polypeptides mayremain intracellularly located or may be secreted by the cancer cell.Moreover, such polypeptides may be expressed not by the cancer cellitself, but rather by cells which produce and/or secrete polypeptideshaving a potentiating or growth-enhancing effect on cancer cells. Suchsecreted polypeptides are often proteins that provide cancer cells witha growth advantage over normal cells and include such things as, forexample, angiogenic factors, cellular adhesion factors, growth factors,and the like. Identification of antagonists of such non-membraneassociated polypeptides would be expected to serve as effectivetherapeutic agents for the treatment of such cancers. Furthermore,identification of the expression pattern of such polypeptides would beuseful for the diagnosis of particular cancers in mammals.

[0006] Despite the above identified advances in mammalian cancertherapy, there is a great need for additional diagnostic and therapeuticagents capable of detecting the presence of tumor in a mammal and foreffectively inhibiting neoplastic cell growth, respectively.Accordingly, it is an objective of the present invention to identify:(1) cell membrane-associated polypeptides that are more abundantlyexpressed on one or more type(s) of cancer cell(s) as compared to onnormal cells or on other different cancer cells, (2)non-membrane-associated polypeptides that are specifically produced byone or more particular type(s) of cancer cell(s) (or by other cells thatproduce polypeptides having a potentiating effect on the growth ofcancer cells) as compared to by one or more particular type(s) ofnon-cancerous normal cell(s), (3) non-membrane-associated polypeptidesthat are produced by cancer cells at an expression level that issignificantly higher than that of one or more normal non-cancerouscell(s), or (4) polypeptides whose expression is specifically limited toonly a single (or very limited number of different) tissue type(s) inboth a cancerous and non-cancerous state (e.g., normal prostate andprostate tumor tissue), and to use those polypeptides, and theirencoding nucleic acids, to produce compositions of matter useful in thetherapeutic treatment and diagnostic detection of cancer in mammals. Itis also an objective of the present invention to identify cellmembrane-associated, secreted or intracellular polypeptides whoseexpression is limited to a single or very limited number of tissues, andto use those polypeptides, and their encoding nucleic acids, to producecompositions of matter useful in the therapeutic treatment anddiagnostic detection of cancer in mammals.

SUMMARY OF THE INVENTION

[0007] A. Embodiments

[0008] In the present specification, Applicants describe for the firsttime the identification of various cellular polypeptides (and theirencoding nucleic acids or fragments thereof) which are expressed to agreater degree on the surface of or by one or more types of cancercell(s) as compared to on the surface of or by one or more types ofnormal non-cancer cells. Alternatively, such polypeptides are expressedby cells which produce and/or secrete polypeptides having a potentiatingor growth-enhancing effect on cancer cells. Again alternatively, suchpolypeptides may not be overexpressed by tumor cells as compared tonormal cells of the same tissue type, but rather may be specificallyexpressed by both tumor cells and normal cells of only a single or verylimited number of tissue types (preferably tissues which are notessential for life, e.g., prostate, etc.). All of the above polypeptidesare herein referred to as Tumor-associated Antigenic Target polypeptides(“TAT” polypeptides) and are expected to serve as effective targets forcancer therapy and diagnosis in mammals.

[0009] Accordingly, in one embodiment of the present invention, theinvention provides an isolated nucleic acid molecule having a nucleotidesequence that encodes a tumor-associated antigenic target polypeptide orfragment thereof (a “TAT” polypeptide).

[0010] In certain aspects, the isolated nucleic acid molecule comprisesa nucleotide sequence having at least about 80% nucleic acid sequenceidentity, alternatively at least about 81%, 82%, 83%, 84%, 85%, 86%,87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%nucleic acid sequence identity, to (a) a DNA molecule encoding afull-length TAT polypeptide having an amino acid sequence as disclosedherein, a TAT polypeptide amino acid sequence lacking the signal peptideas disclosed herein, an extracellular domain of a transmembrane TATpolypeptide, with or without the signal peptide, as disclosed herein orany other specifically defined fragment of a full-length TAT polypeptideamino acid sequence as disclosed herein, or (b) the complement of theDNA molecule of (a).

[0011] In other aspects, the isolated nucleic acid molecule comprises anucleotide sequence having at least about 80% nucleic acid sequenceidentity, alternatively at least about 81%, 82%, 83%, 84%, 85%, 86%,87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%nucleic acid sequence identity, to (a) a DNA molecule comprising thecoding sequence of a full-length TAT polypeptide cDNA as disclosedherein, the coding sequence of a TAT polypeptide lacking the signalpeptide as disclosed herein, the coding sequence of an extracellulardomain of a transmembrane TAT polypeptide, with or without the signalpeptide, as disclosed herein or the coding sequence of any otherspecifically defined fragment of the full-length TAT polypeptide aminoacid sequence as disclosed herein, or (b) the complement of the DNAmolecule of (a).

[0012] In further aspects, the invention concerns an isolated nucleicacid molecule comprising a nucleotide sequence having at least about 80%nucleic acid sequence identity, alternatively at least about 81%, 82%,83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99% or 100% nucleic acid sequence identity, to (a) a DNAmolecule that encodes the same mature polypeptide encoded by thefull-length coding region of any of the human protein cDNAs depositedwith the ATCC as disclosed herein, or (b) the complement of the DNAmolecule of (a).

[0013] Another aspect of the invention provides an isolated nucleic acidmolecule comprising a nucleotide sequence encoding a TAT polypeptidewhich is either transmembrane domain-deleted or transmembranedomain-inactivated, or is complementary to such encoding nucleotidesequence, wherein the transmembrane domain(s) of such polypeptide(s) aredisclosed herein. Therefore, soluble extracellular domains of the hereindescribed TAT polypeptides are contemplated.

[0014] In other aspects, the present invention is directed to isolatednucleic acid molecules which hybridize to (a) a nucleotide sequenceencoding a TAT polypeptide having a full-length amino acid sequence asdisclosed herein, a TAT polypeptide amino acid sequence lacking thesignal peptide as disclosed herein, an extracellular domain of atransmembrane TAT polypeptide, with or without the signal peptide, asdisclosed herein or any other specifically defined fragment of afull-length TAT polypeptide amino acid sequence as disclosed herein, or(b) the complement of the nucleotide sequence of (a). In this regard, anembodiment of the present invention is directed to fragments of afull-length TAT polypeptide coding sequence, or the complement thereof,as disclosed herein, that may find use as, for example, hybridizationprobes useful as, for example, diagnostic probes, antisenseoligonucleotide probes, or for encoding fragments of a full-length TATpolypeptide that may optionally encode a polypeptide comprising abinding site for an anti-TAT polypeptide antibody, a TAT bindingoligopeptide or other small organic molecule that binds to a TATpolypeptide. Such nucleic acid fragments are usually at least about 5nucleotides in length, alternatively at least about 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90,95, 100, 105, 110,115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180,185, 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300,310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440,450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580,590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720,730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860,870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000nucleotides in length, wherein in this context the term “about” meansthe referenced nucleotide sequence length plus or minus 10% of thatreferenced length. It is noted that novel fragments of a TATpolypeptide-encoding nucleotide sequence may be determined in a routinemanner by aligning the TAT polypeptide-encoding nucleotide sequence withother known nucleotide sequences using any of a number of well knownsequence alignment programs and determining which TATpolypeptide-encoding nucleotide sequence fragment(s) are novel. All ofsuch novel fragments of TAT polypeptide-encoding nucleotide sequencesare contemplated herein. Also contemplated are the TAT polypeptidefragments encoded by these nucleotide molecule fragments, preferablythose TAT polypeptide fragments that comprise a binding site for ananti-TAT antibody, a TAT binding oligopeptide or other small organicmolecule that binds to a TAT polypeptide.

[0015] In another embodiment, the invention provides isolated TATpolypeptides encoded by any of the isolated nucleic acid sequenceshereinabove identified.

[0016] In a certain aspect, the invention concerns an isolated TATpolypeptide, comprising an amino acid sequence having at least about 80%amino acid sequence identity, alternatively at least about 81%, 82%,83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, 99% or 100% amino acid sequence identity, to a TAT polypeptidehaving a full-length amino acid sequence as disclosed herein, a TATpolypeptide amino acid sequence lacking the signal peptide as disclosedherein, an extracellular domain of a transmembrane TAT polypeptideprotein, with or without the signal peptide, as disclosed herein, anamino acid sequence encoded by any of the nucleic acid sequencesdisclosed herein or any other specifically defined fragment of afull-length TAT polypeptide amino acid sequence as disclosed herein.

[0017] In a further aspect, the invention concerns an isolated TATpolypeptide comprising an amino acid sequence having at least about 80%amino acid sequence identity, alternatively at least about 81%, 82%,83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, or 99% amino acid sequence identity, to an amino acid sequenceencoded by any of the human protein cDNAs deposited with the ATCC asdisclosed herein.

[0018] In a specific aspect, the invention provides an isolated TATpolypeptide without the N-terminal signal sequence and/or without theinitiating methionine and is encoded by a nucleotide sequence thatencodes such an amino acid sequence as hereinbefore described. Processesfor producing the same are also herein described, wherein thoseprocesses comprise culturing a host cell comprising a vector whichcomprises the appropriate encoding nucleic acid molecule underconditions suitable for expression of the TAT polypeptide and recoveringthe TAT polypeptide from the cell culture.

[0019] Another aspect of the invention provides an isolated TATpolypeptide which is either transmembrane domain-deleted ortransmembrane domain-inactivated. Processes for producing the same arealso herein described, wherein those processes comprise culturing a hostcell comprising a vector which comprises the appropriate encodingnucleic acid molecule under conditions suitable for expression of theTAT polypeptide and recovering the TAT polypeptide from the cellculture.

[0020] In other embodiments of the present invention, the inventionprovides vectors comprising DNA encoding any of the herein describedpolypeptides. Host cells comprising any such vector are also provided.By way of example, the host cells may be CHO cells, E. coli cells, oryeast cells. A process for producing any of the herein describedpolypeptides is further provided and comprises culturing host cellsunder conditions suitable for expression of the desired polypeptide andrecovering the desired polypeptide from the cell culture.

[0021] In other embodiments, the invention provides isolated chimericpolypeptides comprising any of the herein described TAT polypeptidesfused to a heterologous (non-TAT) polypeptide. Example of such chimericmolecules comprise any of the herein described TAT polypeptides fused toa heterologous polypeptide such as, for example, an epitope tag sequenceor a Fc region of an immunoglobulin.

[0022] In another embodiment, the invention provides an antibody whichbinds, preferably specifically, to any of the above or below describedpolypeptides. Optionally, the antibody is a monoclonal antibody,antibody fragment, chimeric antibody, humanized antibody, single-chainantibody or antibody that competitively inhibits the binding of ananti-TAT polypeptide antibody to its respective antigenic epitope.Antibodies of the present invention may optionally be conjugated to agrowth inhibitory agent or cytotoxic agent such as a toxin, including,for example, a maytansinoid or calicheamicin, an antibiotic, aradioactive isotope, a nucleolytic enzyme, or the like. The antibodiesof the present invention may optionally be produced in CHO cells orbacterial cells and preferably induce death of a cell to which theybind. For diagnostic purposes, the antibodies of the present inventionmay be detectably labeled, attached to a solid support, or the like.

[0023] In other embodiments of the present invention, the inventionprovides vectors comprising DNA encoding any of the herein describedantibodies. Host cell comprising any such vector are also provided. Byway of example, the host cells may be CHO cells, E. coli cells, or yeastcells. A process for producing any of the herein described antibodies isfurther provided and comprises culturing host cells under conditionssuitable for expression of the desired antibody and recovering thedesired antibody from the cell culture.

[0024] In another embodiment, the invention provides oligopeptides (“TATbinding oligopeptides”) which bind, preferably specifically, to any ofthe above or below described TAT polypeptides. Optionally, the TATbinding oligopeptides of the present invention may be conjugated to agrowth inhibitory agent or cytotoxic agent such as a toxin, including,for example, a maytansinoid or calicheamicin, an antibiotic, aradioactive isotope, a nucleolytic enzyme, or the like. The TAT bindingoligopeptides of the present invention may optionally be produced in CHOcells or bacterial cells and preferably induce death of a cell to whichthey bind. For diagnostic purposes, the TAT binding oligopeptides of thepresent invention may be detectably labeled, attached to a solidsupport, or the like.

[0025] In other embodiments of the present invention, the inventionprovides vectors comprising DNA encoding any of the herein described TATbinding oligopeptides. Host cell comprising any such vector are alsoprovided. By way of example, the host cells may be CHO cells, E. colicells, or yeast cells. A process for producing any of the hereindescribed TAT binding oligopeptides is further provided and comprisesculturing host cells under conditions suitable for expression of thedesired oligopeptide and recovering the desired oligopeptide from thecell culture.

[0026] In another embodiment, the invention provides small organicmolecules (“TAT binding organic molecules”) which bind, preferablyspecifically, to any of the above or below described TAT polypeptides.Optionally, the TAT binding organic molecules of the present inventionmay be conjugated to a growth inhibitory agent or cytotoxic agent suchas a toxin, including, for example, a maytansinoid or calicheamicin, anantibiotic, a radioactive isotope, a nucleolytic enzyme, or the like.The TAT binding organic molecules of the present invention preferablyinduce death of a cell to which they bind. For diagnostic purposes, theTAT binding organic molecules of the present invention may be detectablylabeled, attached to a solid support, or the like.

[0027] In a still further embodiment, the invention concerns acomposition of matter comprising a TAT polypeptide as described herein,a chimeric TAT polypeptide as described herein, an anti-TAT antibody asdescribed herein, a TAT binding oligopeptide as described herein, or aTAT binding organic molecule as described herein, in combination with acarrier. Optionally, the carrier is a pharmaceutically acceptablecarrier.

[0028] In yet another embodiment, the invention concerns an article ofmanufacture comprising a container and a composition of matter containedwithin the container, wherein the composition of matter may comprise aTAT polypeptide as described herein, a chimeric TAT polypeptide asdescribed herein, an anti-TAT antibody as described herein, a TATbinding oligopeptide as described herein, or a TAT binding organicmolecule as described herein. The article may further optionallycomprise a label affixed to the container, or a package insert includedwith the container, that refers to the use of the composition of matterfor the therapeutic treatment or diagnostic detection of a tumor.

[0029] Another embodiment of the present invention is directed to theuse of a TAT polypeptide as described herein, a chimeric TAT polypeptideas described herein, an anti-TAT polypeptide antibody as describedherein, a TAT binding oligopeptide as described herein, or a TAT bindingorganic molecule as described herein, for the preparation of amedicament useful in the treatment of a condition which is responsive tothe TAT polypeptide, chimeric TAT polypeptide, anti-TAT polypeptideantibody, TAT binding oligopeptide, or TAT binding organic molecule.

[0030] B. Additional Embodiments

[0031] Another embodiment of the present invention is directed to amethod for inhibiting the growth of a cell that expresses a TATpolypeptide, wherein the method comprises contacting the cell with anantibody, an oligopeptide or a small organic molecule that binds to theTAT polypeptide, and wherein the binding of the antibody, oligopeptideor organic molecule to the TAT polypeptide causes inhibition of thegrowth of the cell expressing the TAT polypeptide. In preferredembodiments, the cell is a cancer cell and binding of the antibody,oligopeptide or organic molecule to the TAT polypeptide causes death ofthe cell expressing the TAT polypeptide. Optionally, the antibody is amonoclonal antibody, antibody fragment, chimeric antibody, humanizedantibody, or single-chain antibody. Antibodies, TAT bindingoligopeptides and TAT binding organic molecules employed in the methodsof the present invention may optionally be conjugated to a growthinhibitory agent or cytotoxic agent such as a toxin, including, forexample, a maytansinoid or calicheamicin, an antibiotic, a radioactiveisotope, a nucleolytic enzyme, or the like. The antibodies and TATbinding oligopeptides employed in the methods of the present inventionmay optionally be produced in CHO cells or bacterial cells.

[0032] Yet another embodiment of the present invention is directed to amethod of therapeutically treating a mammal having a cancerous tumorcomprising cells that express a TAT polypeptide, wherein the methodcomprises administering to the mammal a therapeutically effective amountof an antibody, an oligopeptide or a small organic molecule that bindsto the TAT polypeptide, thereby resulting in the effective therapeutictreatment of the tumor. Optionally, the antibody is a monoclonalantibody, antibody fragment, chimeric antibody, humanized antibody, orsingle-chain antibody. Antibodies, TAT binding oligopeptides and TATbinding organic molecules employed in the methods of the presentinvention may optionally be conjugated to a growth inhibitory agent orcytotoxic agent such as a toxin, including, for example, a maytansinoidor calicheamicin, an antibiotic, a radioactive isotope, a nucleolyticenzyme, or the like. The antibodies and oligopeptides employed in themethods of the present invention may optionally be produced in CHO cellsor bacterial cells.

[0033] Yet another embodiment of the present invention is directed to amethod of determining the presence of a TAT polypeptide in a samplesuspected of containing the TAT polypeptide, wherein the methodcomprises exposing the sample to an antibody, oligopeptide or smallorganic molecule that binds to the TAT polypeptide and determiningbinding of the antibody, oligopeptide or organic molecule to the TATpolypeptide in the sample, wherein the presence of such binding isindicative of the presence of the TAT polypeptide in the sample.Optionally, the sample may contain cells (which may be cancer cells)suspected of expressing the TAT polypeptide. The antibody, TAT bindingoligopeptide or TAT binding organic molecule employed in the method mayoptionally be detectably labeled, attached to a solid support, or thelike.

[0034] A further embodiment of the present invention is directed to amethod of diagnosing the presence of a tumor in a mammal, wherein themethod comprises detecting the level of expression of a gene encoding aTAT polypeptide (a) in a test sample of tissue cells obtained from saidmammal, and (b) in a control sample of known normal non-cancerous cellsof the same tissue origin or type, wherein a higher level of expressionof the TAT polypeptide in the test sample, as compared to the controlsample, is indicative of the presence of tumor in the mammal from whichthe test sample was obtained.

[0035] Another embodiment of the present invention is directed to amethod of diagnosing the presence of a tumor in a mammal, wherein themethod comprises (a) contacting a test sample comprising tissue cellsobtained from the mammal with an antibody, oligopeptide or small organicmolecule that binds to a TAT polypeptide and (b) detecting the formationof a complex between the antibody, oligopeptide or small organicmolecule and the TAT polypeptide in the test sample, wherein theformation of a complex is indicative of the presence of a tumor in themammal. Optionally, the antibody, TAT binding oligopeptide or TATbinding organic molecule employed is detectably labeled, attached to asolid support, or the like, and/or the test sample of tissue cells isobtained from an individual suspected of having a cancerous tumor.

[0036] Yet another embodiment of the present invention is directed to amethod for treating or preventing a cell proliferative disorderassociated with altered, preferably increased, expression or activity ofa TAT polypeptide, the method comprising administering to a subject inneed of such treatment an effective amount of an antagonist of a TATpolypeptide. Preferably, the cell proliferative disorder is cancer andthe antagonist of the TAT polypeptide is an anti-TAT polypeptideantibody, TAT binding oligopeptide, TAT binding organic molecule orantisense oligonucleotide. Effective treatment or prevention of the cellproliferative disorder may be a result of direct killing or growthinhibition of cells that express a TAT polypeptide or by antagonizingthe cell growth potentiating activity of a TAT polypeptide.

[0037] Yet another embodiment of the present invention is directed to amethod of binding an antibody, oligopeptide or small organic molecule toa cell that expresses a TAT polypeptide, wherein the method comprisescontacting a cell that expresses a TAT polypeptide with said antibody,oligopeptide or small organic molecule under conditions which aresuitable for binding of the antibody, oligopeptide or small organicmolecule to said TAT polypeptide and allowing binding therebetween.

[0038] Other embodiments of the present invention are directed to theuse of (a) a TAT polypeptide, (b) a nucleic acid encoding a TATpolypeptide or a vector or host cell comprising that nucleic acid, (c)an anti-TAT polypeptide antibody, (d) a TAT-binding oligopeptide, or (e)a TAT-binding small organic molecule in the preparation of a medicamentuseful for (i) the therapeutic treatment or diagnostic detection of acancer or tumor, or (ii) the therapeutic treatment or prevention of acell proliferative disorder.

[0039] Another embodiment of the present invention is directed to amethod for inhibiting the growth of a cancer cell, wherein the growth ofsaid cancer cell is at least in part dependent upon the growthpotentiating effect(s) of a TAT polypeptide (wherein the TAT polypeptidemay be expressed either by the cancer cell itself or a cell thatproduces polypeptide(s) that have a growth potentiating effect on cancercells), wherein the method comprises contacting the TAT polypeptide withan antibody, an oligopeptide or a small organic molecule that binds tothe TAT polypeptide, thereby antagonizing the growth-potentiatingactivity of the TAT polypeptide and, in turn, inhibiting the growth ofthe cancer cell. Preferably the growth of the cancer cell is completelyinhibited. Even more preferably, binding of the antibody, oligopeptideor small organic molecule to the TAT polypeptide induces the death ofthe cancer cell. Optionally, the antibody is a monoclonal antibody,antibody fragment, chimeric antibody, humanized antibody, orsingle-chain antibody. Antibodies, TAT binding oligopeptides and TATbinding organic molecules employed in the methods of the presentinvention may optionally be conjugated to a growth inhibitory agent orcytotoxic agent such as a toxin, including, for example, a maytansinoidor calicheamicin, an antibiotic, a radioactive isotope, a nucleolyticenzyme, or the like. The antibodies and TAT binding oligopeptidesemployed in the methods of the present invention may optionally beproduced in CHO cells or bacterial cells.

[0040] Yet another embodiment of the present invention is directed to amethod of therapeutically treating a tumor in a mammal, wherein thegrowth of said tumor is at least in part dependent upon the growthpotentiating effect(s) of a TAT polypeptide, wherein the methodcomprises administering to the mammal a therapeutically effective amountof an antibody, an oligopeptide or a small organic molecule that bindsto the TAT polypeptide, thereby antagonizing the growth potentiatingactivity of said TAT polypeptide and resulting in the effectivetherapeutic treatment of the tumor. Optionally, the antibody is amonoclonal antibody, antibody fragment, chimeric antibody, humanizedantibody, or single-chain antibody. Antibodies, TAT bindingoligopeptides and TAT binding organic molecules employed in the methodsof the present invention may optionally be conjugated to a growthinhibitory agent or cytotoxic agent such as a toxin, including, forexample, a maytansinoid or calicheamicin, an antibiotic, a radioactiveisotope, a nucleolytic enzyme, or the like. The antibodies andoligopeptides employed in the methods of the present invention mayoptionally be produced in CHO cells or bacterial cells.

[0041] C. Further Additional Embodiments

[0042] In yet further embodiments, the invention is directed to thefollowing set of potential claims for this application:

[0043] 1. Isolated nucleic acid having a nucleotide sequence that has atleast 80% nucleic acid sequence identity to:

[0044] (a) a DNA molecule encoding the amino acid sequence shown in anyone of FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116,118 or 120);

[0045] (b) a DNA molecule encoding the amino acid sequence shown in anyone of FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116,118 or 120), lacking its associated signal peptide;

[0046] (c) a DNA molecule encoding an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), with its associated signalpeptide;

[0047] (d) a DNA molecule encoding an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118or 120), lacking its associated signalpeptide;

[0048] (e) the nucleotide sequence shown in any one of FIGS. 1-56, 113,115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117 or 119);

[0049] (f) the full-length coding region of the nucleotide sequenceshown in any one of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56,113, 115, 117 or 119); or

[0050] (g) the complement of (a), (b), (c), (d), (e) or (f).

[0051] 2. Isolated nucleic acid having:

[0052] (a) a nucleotide sequence that encodes the amino acid sequenceshown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQ IDNOS:57-112, 114, 116, 118 or 120);

[0053] (b) a nucleotide sequence that encodes the amino acid sequenceshown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQ IDNOS:57-112, 114, 116, 118 or 120), lacking its associated signalpeptide;

[0054] (c) a nucleotide sequence that encodes an extracellular domain ofthe polypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120(SEQ ID NOS:57-112, 114, 116, 118 or 120), with its associated signalpeptide;

[0055] (d) a nucleotide sequence that encodes an extracellular domain ofthe polypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120(SEQ ID NOS:57-112, 114, 116, 118 or 120), lacking its associated signalpeptide;

[0056] (e) the nucleotide sequence shown in any one of FIGS. 1-56, 113,115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117 or 119);

[0057] (f) the full-length coding region of the nucleotide sequenceshown in any one of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56,113, 115, 117 or 119); or

[0058] (g) the complement of (a), (b), (c), (d), (e) or (f).

[0059] 3. Isolated nucleic acid that hybridizes to:

[0060] (a) a nucleic acid that encodes the amino acid sequence shown inany one of FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114,116, 118 or 120);

[0061] (b) a nucleic acid that encodes the amino acid sequence shown inany one of FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114,116, 118 or 120), lacking its associated signal peptide;

[0062] (c) a nucleic acid that encodes an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), with its associated signalpeptide;

[0063] (d) a nucleic acid that encodes an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), lacking its associated signalpeptide;

[0064] (e) the nucleotide sequence shown in any one of FIGS. 1-56, 113,115,117 or 119 (SEQ ID NOS:1-56, 113, 115, 117 or 119);

[0065] (f) the full-length coding region of the nucleotide sequenceshown in any one of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56,113, 115, 117 or 119); or

[0066] (g) the complement of (a), (b), (c), (d), (e) or (f).

[0067] 4. The nucleic acid of Claim 3, wherein the hybridization occursunder stringent conditions.

[0068] 5. The nucleic acid of Claim 3 which is at least about 5nucleotides in length.

[0069] 6. An expression vector comprising the nucleic acid of Claim 1, 2or 3.

[0070] 7. The expression vector of Claim 6, wherein said nucleic acid isoperably linked to control sequences recognized by a host celltransformed with the vector.

[0071] 8. A host cell comprising the expression vector of Claim 7.

[0072] 9. The host cell of Claim 8 which is a CHO cell, an E. coli cellor a yeast cell.

[0073] 10. A process for producing a polypeptide comprising culturingthe host cell of Claim 8 under conditions suitable for expression ofsaid polypeptide and recovering said polypeptide from the cell culture.

[0074] 11. An isolated polypeptide having at least 80% amino acidsequence identity to:

[0075] (a) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0076] (b) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lacking itsassociated signal peptide;

[0077] (c) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), with its associated signal peptide;

[0078] (d) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), lacking its associated signal peptide;

[0079] (e) a polypeptide encoded by the nucleotide sequence shown in anyone of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117or 119); or

[0080] (f) a polypeptide encoded by the full-length coding region of thenucleotide sequence shown in any one of FIGS. 1-56, 113, 115, 117 or 119(SEQ ID NOS:1-56, 113, 115, 117 or 119).

[0081] 12. An isolated polypeptide having:

[0082] (a) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-35 112, 114, 116, 118 or 120);

[0083] (b) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lackingits associated signal peptide sequence;

[0084] (c) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), with its associated signal peptidesequence;

[0085] (d) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), lacking its associated signalpeptide sequence;

[0086] (e) an amino acid sequence encoded by the nucleotide sequenceshown in any one of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56,113, 115, 117 or 119); or

[0087] (f) an amino acid sequence encoded by the full-length codingregion of the nucleotide sequence shown in any one of FIGS. 1-56, 113,115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117 or 119).

[0088] 13. A chimeric polypeptide comprising the polypeptide of Claim 11or 12 fused to a heterologous polypeptide.

[0089] 14. The chimeric polypeptide of Claim 13, wherein saidheterologous polypeptide is an epitope tag sequence or an Fc region ofan immunoglobulin.

[0090] 15. An isolated antibody that binds to a polypeptide having atleast 80% amino acid sequence identity to:

[0091] (a) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0092] (b) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lacking itsassociated signal peptide;

[0093] (c) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), with its associated signal peptide;

[0094] (d) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), lacking its associated signal peptide;

[0095] (e) a polypeptide encoded by the nucleotide sequence shown in anyone of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117or 119); or

[0096] (f) a polypeptide encoded by the full-length coding region of thenucleotide sequence shown in any one of FIGS. 1-56, 113, 115, 117 or 119(SEQ ID NOS:1-56, 113, 115, 117 or 119).

[0097] 16. An isolated antibody that binds to a polypeptide having:

[0098] (a) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0099] (b) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lackingits associated signal peptide sequence;

[0100] (c) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), with its associated signal peptidesequence;

[0101] (d) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), lacking its associated signalpeptide sequence;

[0102] (e) an amino acid sequence encoded by the nucleotide sequenceshown in any one of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56,113, 115, 117 or 119); or

[0103] (f) an amino acid sequence encoded by the full-length codingregion of the nucleotide sequence shown in any one of FIGS. 1-56, 113,115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117 or 119).

[0104] 17. The antibody of Claim 15 or 16 which is a monoclonalantibody.

[0105] 18. The antibody of Claim 15 or 16 which is an antibody fragment.

[0106] 19. The antibody of Claim 15 or 16 which is a chimeric or ahumanized antibody.

[0107] 20. The antibody of Claim 15 or 16 which is conjugated to agrowth inhibitory agent.

[0108] 21. The antibody of Claim 15 or 16 which is conjugated to acytotoxic agent.

[0109] 22. The antibody of Claim 21, wherein the cytotoxic agent isselected from the group consisting of toxins, antibiotics, radioactiveisotopes and nucleolytic enzymes.

[0110] 23. The antibody of Claim 21, wherein the cytotoxic agent is atoxin.

[0111] 24. The antibody of Claim 23, wherein the toxin is selected fromthe group consisting of maytansinoid and calicheamicin.

[0112] 25. The antibody of Claim 23, wherein the toxin is amaytansinoid.

[0113] 26. The antibody of Claim 15 or 16 which is produced in bacteria.

[0114] 27. The antibody of Claim 15 or 16 which is produced in CHOcells.

[0115] 28. The antibody of Claim 15 or 16 which induces death of a cellto which it binds.

[0116] 29. The antibody of Claim 15 or 16 which is detectably labeled.

[0117] 30. An isolated nucleic acid having a nucleotide sequence thatencodes the antibody of Claim 15 or 16.

[0118] 31. An expression vector comprising the nucleic acid of Claim 30operably linked to control sequences recognized by a host celltransformed with the vector.

[0119] 32. A host cell comprising the expression vector of Claim 31.

[0120] 33. The host cell of Claim 32 which is a CHO cell, an E. colicell or a yeast cell.

[0121] 34. A process for producing an antibody comprising culturing thehost cell of Claim 32 under conditions suitable for expression of saidantibody and recovering said antibody from the cell culture.

[0122] 35. An isolated oligopeptide that binds to a polypeptide havingat least 80% amino acid sequence identity to:

[0123] (a) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120);

[0124] (b) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lacking itsassociated signal peptide;

[0125] (c) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), with its associated signal peptide;

[0126] (d) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), lacking its associated signal peptide;

[0127] (e) a polypeptide encoded by the nucleotide sequence shown in anyone of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117or 119); or

[0128] (f) a polypeptide encoded by the full-length coding region of thenucleotide sequence shown in any one of FIGS. 1-56, 113, 115, 117 or 119(SEQ ID NOS:1-56, 113, 115, 117 or 119).

[0129] 36. An isolated oligopeptide that binds to a polypeptide having:

[0130] (a) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0131] (b) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lackingits associated signal peptide sequence;

[0132] (c) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS: 57-112, 114, 116, 118 or 120), with its associated signalpeptide sequence;

[0133] (d) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), lacking its associated signalpeptide sequence;

[0134] (e) an amino acid sequence encoded by the nucleotide sequenceshown in any one of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56,113, 115, 117 or 119); or

[0135] (f) an amino acid sequence encoded by the full-length codingregion of the nucleotide sequence shown in any one of FIGS. 1-56, 113,115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117 or 119).

[0136] 37. The oligopeptide of Claim 35 or 36 which is conjugated to agrowth inhibitory agent.

[0137] 38. The oligopeptide of Claim 35 or 36 which is conjugated to acytotoxic agent.

[0138] 39. The oligopeptide of Claim 38, wherein the cytotoxic agent isselected from the group consisting of toxins, antibiotics, radioactiveisotopes and nucleolytic enzymes.

[0139] 40. The oligopeptide of Claim 38, wherein the cytotoxic agent isa toxin.

[0140] 41. The oligopeptide of Claim 40, wherein the toxin is selectedfrom the group consisting of maytansinoid and calicheamicin.

[0141] 42. The oligopeptide of Claim 40, wherein the toxin is amaytansinoid.

[0142] 43. The oligopeptide of Claim 35 or 36 which induces death of acell to which it binds.

[0143] 44. The oligopeptide of Claim 35 or 36 which is detectablylabeled.

[0144] 45. A TAT binding organic molecule that binds to a polypeptidehaving at least 80% amino acid sequence identity to:

[0145] (a) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0146] (b) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lacking itsassociated signal peptide;

[0147] (c) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), with its associated signal peptide;

[0148] (d) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), lacking its associated signal peptide;

[0149] (e) a polypeptide encoded by the nucleotide sequence shown in anyone of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117or 119); or

[0150] (f) a polypeptide encoded by the full-length coding region of thenucleotide sequence shown in any one of FIGS. 1-56, 113, 115, 117 or 119(SEQ ID NOS:1-56, 113, 115, 117 or 119).

[0151] 46. The organic molecule of Claim 45 that binds to a polypeptidehaving:

[0152] (a) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0153] (b) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lackingits associated signal peptide sequence;

[0154] (c) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), with its associated signal peptidesequence;

[0155] (d) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), lacking its associated signalpeptide sequence;

[0156] (e) an amino acid sequence encoded by the nucleotide sequenceshown in any one of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56,113, 115, 117 or 119); or

[0157] (f) an amino acid sequence encoded by the full-length codingregion of the nucleotide sequence shown in any one of FIGS. 1-56, 113,115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117 or 119).

[0158] 47. The organic molecule of Claim 45 or 46 which is conjugated toa growth inhibitory agent.

[0159] 48. The organic molecule of Claim 45 or 46 which is conjugated toa cytotoxic agent.

[0160] 49. The organic molecule of Claim 48, wherein the cytotoxic agentis selected from the group consisting of toxins, antibiotics,radioactive isotopes and nucleolytic enzymes.

[0161] 50. The organic molecule of Claim 48, wherein the cytotoxic agentis a toxin.

[0162] 51. The organic molecule of Claim 50, wherein the toxin isselected from the group consisting of maytansinoid and calicheamicin.

[0163] 52. The organic molecule of Claim 50, wherein the toxin is amaytansinoid.

[0164] 53. The organic molecule of Claim 45 or 46 which induces death ofa cell to which it binds.

[0165] 54. The organic molecule of Claim 45 or 46 which is detectablylabeled.

[0166] 55. A composition of matter comprising:

[0167] (a) the polypeptide of Claim 11;

[0168] (b) the polypeptide of Claim 12;

[0169] (c) the chimeric polypeptide of Claim 13;

[0170] (d) the antibody of Claim 15;

[0171] (e) the antibody of Claim 16;

[0172] (f) the oligopeptide of Claim 35;

[0173] (g) the oligopeptide of Claim 36;

[0174] (h) the TAT binding organic molecule of Claim 45; or

[0175] (i) the TAT binding organic molecule of Claim 46; in combinationwith a carrier.

[0176] 56. The composition of matter of Claim 55, wherein said carrieris a pharmaceutically acceptable carrier.

[0177] 57. An article of manufacture comprising:

[0178] (a) a container; and

[0179] (b) the composition of matter of Claim 55 contained within saidcontainer.

[0180] 58. The article of manufacture of Claim 57 further comprising alabel affixed to said container, or a package insert included with saidcontainer, referring to the use of said composition of matter for thetherapeutic treatment of or the diagnostic detection of a cancer.

[0181] 59. A method of inhibiting the growth of a cell that expresses aprotein having at least 80% amino acid sequence identity to:

[0182] (a) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0183] (b) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lacking itsassociated signal peptide;

[0184] (c) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), with its associated signal peptide;

[0185] (d) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), lacking its associated signal peptide;

[0186] (e) a polypeptide encoded by the nucleotide sequence shown in anyone of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117or 119); or

[0187] (f) a polypeptide encoded by the full-length coding region of thenucleotide sequence shown in any one of FIGS. 1-56, 113, 115, 117 or 119(SEQ ID NOS:1-56, 113, 115, 117 or 119), said method comprisingcontacting said cell with an antibody, oligopeptide or organic moleculethat binds to said protein, the binding of said antibody, oligopeptideor organic molecule to said protein thereby causing an inhibition ofgrowth of said cell.

[0188] 60. The method of Claim 59, wherein said antibody is a monoclonalantibody.

[0189] 61. The method of Claim 59, wherein said antibody is an antibodyfragment.

[0190] 62. The method of Claim 59, wherein said antibody is a chimericor a humanized antibody.

[0191] 63. The method of Claim 59, wherein said antibody, oligopeptideor organic molecule is conjugated to a growth inhibitory agent.

[0192] 64. The method of Claim 59, wherein said antibody, oligopeptideor organic molecule is conjugated to a cytotoxic agent.

[0193] 65. The method of Claim 64, wherein said cytotoxic agent isselected from the group consisting of toxins, antibiotics, radioactiveisotopes and nucleolytic enzymes.

[0194] 66. The method of Claim 64, wherein the cytotoxic agent is atoxin.

[0195] 67. The method of Claim 66, wherein the toxin is selected fromthe group consisting of maytansinoid and calicheamicin.

[0196] 68. The method of Claim 66, wherein the toxin is a maytansinoid.

[0197] 69. The method of Claim 59, wherein said antibody is produced inbacteria.

[0198] 70. The method of Claim 59, wherein said antibody is produced inCHO cells.

[0199] 71. The method of Claim 59, wherein said cell is a cancer cell.

[0200] 72. The method of Claim 71, wherein said cancer cell is furtherexposed to radiation treatment or a chemotherapeutic agent.

[0201] 73. The method of Claim 71, wherein said cancer cell is selectedfrom the group consisting of a breast cancer cell, a colorectal cancercell, a lung cancer cell, an ovarian cancer cell, a central nervoussystem cancer cell, a liver cancer cell, a bladder cancer cell, apancreatic cancer cell, a cervical cancer cell, a melanoma cell and aleukemia cell.

[0202] 74. The method of Claim 71, wherein said protein is moreabundantly expressed by said cancer cell as compared to a normal cell ofthe same tissue origin.

[0203] 75. The method of Claim 59 which causes the death of said cell.

[0204] 76. The method of Claim 59, wherein said protein has:

[0205] (a) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0206] (b) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lackingits associated signal peptide sequence;

[0207] (c) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), with its associated signal peptidesequence;

[0208] (d) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), lacking its associated signalpeptide sequence;

[0209] (e) an amino acid sequence encoded by the nucleotide sequenceshown in any one of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56,113, 115, 117 or 119); or

[0210] (f) an amino acid sequence encoded by the full-length codingregion of the nucleotide sequence shown in any one of FIGS. 1-56, 113,115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117 or 119).

[0211] 77. A method of therapeutically treating a mammal having acancerous tumor comprising cells that express a protein having at least80% amino acid sequence identity to:

[0212] (a) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0213] (b) the polypeptide shown in any one of FIGS. 7-112, 114, 116,118 or 120 (SEQ ID NOS: 57-112, 114, 116, 118 or 120), lacking itsassociated signal peptide;

[0214] (c) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), with its associated signal peptide;

[0215] (d) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), lacking its associated signal peptide;

[0216] (e) a polypeptide encoded by the nucleotide sequence shown in anyone of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117or 119); or

[0217] (f) a polypeptide encoded by the full-length coding region of thenucleotide sequence shown in any one of FIGS. 1-56, 113, 115, 117 or 119(SEQ ID NOS:1-56, 113, 115, 117 or 119), said method comprisingadministering to said mammal a therapeutically effective amount of anantibody, oligopeptide or organic molecule that binds to said protein,thereby effectively treating said mammal.

[0218] 78. The method of Claim 77, wherein said antibody is a monoclonalantibody.

[0219] 79. The method of Claim 77, wherein said antibody is an antibodyfragment.

[0220] 80. The method of Claim 77, wherein said antibody is a chimericor a humanized antibody.

[0221] 81. The method of Claim 77, wherein said antibody, oligopeptideor organic molecule is conjugated to a growth inhibitory agent.

[0222] 82. The method of Claim 77, wherein said antibody, oligopeptideor organic molecule is conjugated to a cytotoxic agent.

[0223] 83. The method of Claim 82, wherein said cytotoxic agent isselected from the group consisting of toxins, antibiotics, radioactiveisotopes and nucleolytic enzymes.

[0224] 84. The method of Claim 82, wherein the cytotoxic agent is atoxin.

[0225] 85. The method of Claim 84, wherein the toxin is selected fromthe group consisting of maytansinoid and calicheamicin.

[0226] 86. The method of Claim 84, wherein the toxin is a maytansinoid.

[0227] 87. The method of Claim 77, wherein said antibody is produced inbacteria.

[0228] 88. The method of Claim 77, wherein said antibody is produced inCHO cells.

[0229] 89. The method of Claim 77, wherein said tumor is further exposedto radiation treatment or a chemotherapeutic agent.

[0230] 90. The method of Claim 77, wherein said tumor is a breast tumor,a colorectal tumor, a lung tumor, an ovarian tumor, a central nervoussystem tumor, a liver tumor, a bladder tumor, a pancreatic tumor, or acervical tumor.

[0231] 91. The method of Claim 77, wherein said protein is moreabundantly expressed by the cancerous cells of said tumor as compared toa normal cell of the same tissue origin.

[0232] 92. The method of Claim 77, wherein said protein has:

[0233] (a) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0234] (b) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lackingits associated signal peptide sequence;

[0235] (c) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), with its associated signal peptidesequence;

[0236] (d) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), lacking its associated signalpeptide sequence;

[0237] (e) an amino acid sequence encoded by the nucleotide sequenceshown in any one of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56,113, 115, 117 or 119); or

[0238] (f) an amino acid sequence encoded by the full-length codingregion of the nucleotide sequence shown in any one of FIGS. 1-56, 113,115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117 or 119).

[0239] 93. A method of determining the presence of a protein in a samplesuspected of containing said protein, wherein said protein has at least80% amino acid sequence identity to:

[0240] (a) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0241] (b) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lacking itsassociated signal peptide;

[0242] (c) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57- 112, 114, 116, 118or 120), with its associated signal peptide;

[0243] (d) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), lacking its associated signal peptide;

[0244] (e) a polypeptide encoded by the nucleotide sequence shown in anyone of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117or 119); or

[0245] (f) a polypeptide encoded by the full-length coding region of thenucleotide sequence shown in any one of FIGS. 1-56, 113, 115, 117 or 119(SEQ ID NOS:1-56, 113, 115, 117 or 119), said method comprising exposingsaid sample to an antibody, oligopeptide or organic molecule that bindsto said protein and determining binding of said antibody, oligopeptideor organic molecule to said protein in said sample, wherein binding ofthe antibody, oligopeptide or organic molecule to said protein isindicative of the presence of said protein in said sample.

[0246] 94. The method of Claim 93, wherein said sample comprises a cellsuspected of expressing said protein.

[0247] 95. The method of Claim 94, wherein said cell is a cancer cell.

[0248] 96. The method of Claim 93, wherein said antibody, oligopeptideor organic molecule is detectably labeled.

[0249] 97. The method of Claim 93, wherein said protein has:

[0250] (a) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0251] (b) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lackingits associated signal peptide sequence;

[0252] (c) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), with its associated signal peptidesequence;

[0253] (d) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), lacking its associated signalpeptide sequence;

[0254] (e) an amino acid sequence encoded by the nucleotide sequenceshown in any one of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56,113, 115, 117or 119);or

[0255] (f) an amino acid sequence encoded by the full-length codingregion of the nucleotide sequence shown in any one of FIGS. 1-56, 113,115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117 or 119).

[0256] 98. A method of diagnosing the presence of a tumor in a mammal,said method comprising determining the level of expression of a geneencoding a protein having at least 80% amino acid sequence identity to:

[0257] (a) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0258] (b) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lacking itsassociated signal peptide;

[0259] (c) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), with its associated signal peptide;

[0260] (d) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), lacking its associated signal peptide;

[0261] (e) a polypeptide encoded by the nucleotide sequence shown in anyone of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117or 119); or

[0262] (f) a polypeptide encoded by the full-length coding region of thenucleotide sequence shown in any one of FIGS. 1-56, 113, 115, 117 or 119(SEQ ID NOS:1-56, 113, 115, 117 or 119), in a test sample of tissuecells obtained from said mammal and in a control sample of known normalcells of the same tissue origin, wherein a higher level of expression ofsaid protein in the test sample, as compared to the control sample, isindicative of the presence of tumor in the mammal from which the testsample was obtained.

[0263] 99. The method of Claim 98, wherein the step of determining thelevel of expression of a gene encoding said protein comprises employingan oligonucleotide in an in situ hybridization or RT-PCR analysis.

[0264] 100. The method of Claim 98, wherein the step determining thelevel of expression of a gene encoding said protein comprises employingan antibody in an immunohistochemistry or Western blot analysis.

[0265] 101. The method of Claim 98, wherein said protein has:

[0266] (a) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0267] (b) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lackingits associated signal peptide sequence;

[0268] (c) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), with its associated signal peptidesequence;

[0269] (d) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), lacking its associated signalpeptide sequence;

[0270] (e) an amino acid sequence encoded by the nucleotide sequenceshown in any one of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56,113, 115, 117 or 119); or

[0271] (f) an amino acid sequence encoded by the full-length codingregion of the nucleotide sequence shown in any one of FIGS. 1-56, 113,115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117 or 119).

[0272] 102. A method of diagnosing the presence of a tumor in a mammal,said method comprising contacting a test sample of tissue cells obtainedfrom said mammal with an antibody, oligopeptide or organic molecule thatbinds to a protein having at least 80% amino acid sequence identity to:

[0273] (a) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0274] (b) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lacking itsassociated signal peptide;

[0275] (c) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), with its associated signal peptide;

[0276] (d) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), lacking its associated signal peptide;

[0277] (e) a polypeptide encoded by the nucleotide sequence shown in anyone of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117or 119); or

[0278] (f) a polypeptide encoded by the full-length coding region of thenucleotide sequence shown in any one of FIGS. 1-56, 113, 115, 117 or 119(SEQ ID NOS:1-56, 113, 115, 117 or 119), and detecting the formation ofa complex between said antibody, oligopeptide or organic molecule andsaid protein in the test sample, wherein the formation of a complex isindicative of the presence of a tumor in said mammal.

[0279] 103. The method of Claim 102, wherein said antibody, oligopeptideor organic molecule is detectably labeled.

[0280] 104. The method of Claim 102, wherein said test sample of tissuecells is obtained from an individual suspected of having a canceroustumor.

[0281] 105. The method of Claim 102, wherein said protein has:

[0282] (a) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0283] (b) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lackingits associated signal peptide sequence;

[0284] (c) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), with its associated signal peptidesequence;

[0285] (d) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), lacking its associated signalpeptide sequence;

[0286] (e) an amino acid sequence encoded by the nucleotide sequenceshown in any one of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56,113, 115, 117 or 119);or

[0287] (f) an amino acid sequence encoded by the full-length codingregion of the nucleotide sequence shown in any one of FIGS. 1-56, 113,115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117 or 119).

[0288] 106. A method for treating or preventing a cell proliferativedisorder associated with increased expression or activity of a proteinhaving at least 80% amino acid sequence identity to:

[0289] (a) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0290] (b) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lacking itsassociated signal peptide;

[0291] (c) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), with its associated signal peptide;

[0292] (d) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), lacking its associated signal peptide;

[0293] (e) a polypeptide encoded by the nucleotide sequence shown in anyone of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117or 119); or

[0294] (f) a polypeptide encoded by the full-length coding region of thenucleotide sequence shown in any one of FIGS. 1-56, 113, 115, 117 or 119(SEQ ID NOS:1-56, 113, 115, 117 or 119), said method comprisingadministering to a subject in need of such treatment an effective amountof an antagonist of said protein, thereby effectively treating orpreventing said cell proliferative disorder.

[0295] 107. The method of Claim 106, wherein said cell proliferativedisorder is cancer.

[0296] 108. The method of Claim 106, wherein said antagonist is ananti-TAT polypeptide antibody, TAT binding oligopeptide, TAT bindingorganic molecule or antisense oligonucleotide.

[0297] 109. A method of binding an antibody, oligopeptide or organicmolecule to a cell that expresses a protein having at least 80% aminoacid sequence identity to:

[0298] (a) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0299] (b) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lacking itsassociated signal peptide;

[0300] (c) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), with its associated signal peptide;

[0301] (d) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), lacking its associated signal peptide;

[0302] (e) a polypeptide encoded by the nucleotide sequence shown in anyone of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117or 119); or

[0303] (f) a polypeptide encoded by the full-length coding region of thenucleotide sequence shown in any one of FIGS. 1-56, 113, 115, 117 or 119(SEQ ID NOS:1-56, 113, 115, 117 or 119), said method comprisingcontacting said cell with an antibody, oligopeptide or organic moleculethat binds to said protein and allowing the binding of the antibody,oligopeptide or organic molecule to said protein to occur, therebybinding said antibody, oligopeptide or organic molecule to said cell.

[0304] 110. The method of Claim 109, wherein said antibody is amonoclonal antibody.

[0305] 111. The method of Claim 109, wherein said antibody is anantibody fragment.

[0306] 112. The method of Claim 109, wherein said antibody is a chimericor a humanized antibody.

[0307] 113. The method of Claim 109, wherein said antibody, oligopeptideor organic molecule is conjugated to a growth inhibitory agent.

[0308] 114. The method of Claim 109, wherein said antibody, oligopeptideor organic molecule is conjugated to a cytotoxic agent.

[0309] 115. The method of Claim 114, wherein said cytotoxic agent isselected from the group consisting of toxins, antibiotics, radioactiveisotopes and nucleolytic enzymes.

[0310] 116. The method of Claim 114, wherein the cytotoxic agent is atoxin.

[0311] 117. The method of Claim 116, wherein the toxin is selected fromthe group consisting of maytansinoid and calicheamicin.

[0312] 118. The method of Claim 116, wherein the toxin is amaytansinoid.

[0313] 119. The method of Claim 109, wherein said antibody is producedin bacteria.

[0314] 120. The method of Claim 109, wherein said antibody is producedin CHO cells.

[0315] 121. The method of Claim 109, wherein said cell is a cancer cell.

[0316] 122. The method of Claim 121, wherein said cancer cell is furtherexposed to radiation treatment or a chemotherapeutic agent.

[0317] 123. The method of Claim 121, wherein said cancer cell isselected from the group consisting of a breast cancer cell, a colorectalcancer cell, a lung cancer cell, an ovarian cancer cell, a centralnervous system cancer cell, a liver cancer cell, a bladder cancer cell,a pancreatic cancer cell, a cervical cancer cell, a melanoma cell and aleukemia cell.

[0318] 124. The method of Claim 123, wherein said protein is moreabundantly expressed by said cancer cell as compared to a normal cell ofthe same tissue origin.

[0319] 125. The method of Claim 109 which causes the death of said cell.

[0320] 126. Use of a nucleic acid as claimed in any of claims 1 to 5 or30 in the preparation of a medicament for the therapeutic treatment ordiagnostic detection of a cancer.

[0321] 127. Use of a nucleic acid as claimed in any of claims 1 to 5 or30 in the preparation of a medicament for treating a tumor.

[0322] 128. Use of a nucleic acid as claimed in any of claims 1 to 5 or30 in the preparation of a medicament for treatment or prevention of acell proliferative disorder.

[0323] 129. Use of an expression vector as claimed in any of claims 6, 7or 31 in the preparation of a medicament for the therapeutic treatmentor diagnostic detection of a cancer.

[0324] 130. Use of an expression vector as claimed in any of claims 6, 7or 31 in the preparation of medicament for treating a tumor.

[0325] 131. Use of an expression vector as claimed in any of claims 6, 7or 31 in the preparation of a medicament for treatment or prevention ofa cell proliferative disorder.

[0326] 132. Use of a host cell as claimed in any of claims 8, 9, 32, or33 in the preparation of a medicament for the therapeutic treatment ordiagnostic detection of a cancer.

[0327] 133. Use of a host cell as claimed in any of claims 8, 9, 32 or33 in the preparation of a medicament for treating a tumor.

[0328] 134. Use of a host cell as claimed in any of claims 8, 9, 32 or33 in the preparation of a medicament for treatment or prevention of acell proliferative disorder.

[0329] 135. Use of a polypeptide as claimed in any of claims 11 to 14 inthe preparation of a medicament for the therapeutic treatment ordiagnostic detection of a cancer.

[0330] 136. Use of a polypeptide as claimed in any of claims 11 to 14 inthe preparation of a medicament for treating a tumor.

[0331] 137. Use of a polypeptide as claimed in any of claims 11 to 14 inthe preparation of a medicament for treatment or prevention of a cellproliferative disorder.

[0332] 138. Use of an antibody as claimed in any of claims 15 to 29 inthe preparation of a medicament for the therapeutic treatment ordiagnostic detection of a cancer.

[0333] 139. Use of an antibody as claimed in any of claims 15 to 29 inthe preparation of a medicament for treating a tumor.

[0334] 140. Use of an antibody as claimed in any of claims 15 to 29 inthe preparation of a medicament for treatment or prevention of a cellproliferative disorder.

[0335] 141. Use of an oligopeptide as claimed in any of claims 35 to 44in the preparation of a medicament for the therapeutic treatment ordiagnostic detection of a cancer.

[0336] 142. Use of an oligopeptide as claimed in any of claims 35 to 44in the preparation of a medicament for treating a tumor.

[0337] 143. Use of an oligopeptide as claimed in any of claims 35 to 44in the preparation of a medicament for treatment or prevention of a cellproliferative disorder.

[0338] 144. Use of a TAT binding organic molecule as claimed in any ofclaims 45 to 54 in the preparation of a medicament for the therapeutictreatment or diagnostic detection of a cancer.

[0339] 145. Use of a TAT binding organic molecule as claimed in any ofclaims 45 to 54 in the preparation of a medicament for treating a tumor.

[0340] 146. Use of a TAT binding organic molecule as claimed in any ofclaims 45 to 54 in the preparation of a medicament for treatment orprevention of a cell proliferative disorder.

[0341] 147. Use of a composition of matter as claimed in any of claims55 or 56 in the preparation of a medicament for the therapeutictreatment or diagnostic detection of a cancer.

[0342] 148. Use of a composition of matter as claimed in any of claims55 or 56 in the preparation of a medicament for treating a tumor.

[0343] 149. Use of a composition of matter as claimed in any of claims55 or 56 in the preparation of a medicament for treatment or preventionof a cell proliferative disorder.

[0344] 150. Use of an article of manufacture as claimed in any of claims57 or 58 in the preparation of a medicament for the therapeutictreatment or diagnostic detection of a cancer.

[0345] 151. Use of an article of manufacture as claimed in any of claims57 or 58 in the preparation of a medicament for treating a tumor.

[0346] 152. Use of an article of manufacture as claimed in any of claims57 or 58 in the preparation of a medicament for treatment or preventionof a cell proliferative disorder.

[0347] 153. A method for inhibiting the growth of a cell, wherein thegrowth of said cell is at least in part dependent upon a growthpotentiating effect of a protein having at least 80% amino acid sequenceidentity to:

[0348] (a) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0349] (b) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lacking itsassociated signal peptide;

[0350] (c) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), with its associated signal peptide;

[0351] (d) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), lacking its associated signal peptide;

[0352] (e) a polypeptide encoded by the nucleotide sequence shown in anyone of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117or 119); or

[0353] (f) a polypeptide encoded by the full-length coding region of thenucleotide sequence shown in any one of FIGS. 1-56, 113, 115, 117 or 119(SEQ ID NOS:1-56, 113, 115, 117 or 119), said method comprisingcontacting said protein with an antibody, oligopeptide or organicmolecule that binds to said protein, there by inhibiting the growth ofsaid cell.

[0354] 154. The method of Claim 153, wherein said cell is a cancer cell.

[0355] 155. The method of Claim 153, wherein said protein is expressedby said cell.

[0356] 156. The method of Claim 153, wherein the binding of saidantibody, oligopeptide or organic molecule to said protein antagonizes acell growth-potentiating activity of said protein.

[0357] 157. The method of Claim 153, wherein the binding of saidantibody, oligopeptide or organic molecule to said protein induces thedeath of said cell.

[0358] 158. The method of Claim 153, wherein said antibody is amonoclonal antibody.

[0359] 159. The method of Claim 153, wherein said antibody is anantibody fragment.

[0360] 160. The method of Claim 153, wherein said antibody is a chimericor a humanized antibody.

[0361] 161. The method of Claim 153, wherein said antibody, oligopeptideor organic molecule is conjugated to a growth inhibitory agent.

[0362] 162. The method of Claim 153, wherein said antibody, oligopeptideor organic molecule is conjugated to a cytotoxic agent.

[0363] 163. The method of Claim 162, wherein said cytotoxic agent isselected from the group consisting of toxins, antibiotics, radioactiveisotopes and nucleolytic enzymes.

[0364] 164. The method of Claim 162, wherein the cytotoxic agent is atoxin.

[0365] 165. The method of Claim 164, wherein the toxin is selected fromthe group consisting of maytansinoid and calicheanicin.

[0366] 166. The method of Claim 164, wherein the toxin is amaytansinoid.

[0367] 167. The method of Claim 153, wherein said antibody is producedin bacteria.

[0368] 168. The method of Claim 153, wherein said antibody is producedin CHO cells.

[0369] 169. The method of Claim 153, wherein said protein has:

[0370] (a) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0371] (b) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lackingits associated signal peptide sequence;

[0372] (c) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), with its associated signal peptidesequence;

[0373] (d) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), lacking its associated signalpeptide sequence;

[0374] (e) an amino acid sequence encoded by the nucleotide sequenceshown in any one of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56,113, 115, 117 or 119); or

[0375] (f) an amino acid sequence encoded by the full-length codingregion of the nucleotide sequence shown in any one of FIGS. 1-56, 113,115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117 or 119).

[0376] 170. A method of therapeutically treating a tumor in a mammal,wherein the growth of said tumor is at least in part dependent upon agrowth potentiating effect of a protein having at least 80% amino acidsequence identity to:

[0377] (a) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0378] (b) the polypeptide shown in any one of FIGS. 57-112, 114, 116,118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lacking itsassociated signal peptide;

[0379] (c) an extracellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), with its associated signal peptide;

[0380] (d) an extra cellular domain of the polypeptide shown in any oneof FIGS. 57-112, 114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118or 120), lacking its associated signal peptide;

[0381] (e) a polypeptide encoded by the nucleotide sequence shown in anyone of FIGS. 1-56, 113, 115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117or 119); or

[0382] (f) a polypeptide encoded by the full-length coding region of thenucleotide sequence shown in any one of FIGS. 1-56, 113, 115, 117 or 119(SEQ ID NOS:1-56, 113, 115, 117 or 119), said method comprisingcontacting said protein with an antibody, oligopeptide or organicmolecule that binds to said protein, thereby effectively treating saidtumor.

[0383] 171. The method of Claim 170, wherein said protein is expressedby cells of said tumor.

[0384] 172. The method of Claim 170, wherein the binding of saidantibody, oligopeptide or organic molecule to said protein antagonizes acell growth-potentiating activity of said protein.

[0385] 173. The method of Claim 170, wherein said antibody is amonoclonal antibody.

[0386] 174. The method of Claim 170, wherein said antibody is anantibody fragment.

[0387] 175. The method of Claim 170, wherein said antibody is a chimericor a humanized antibody.

[0388] 176. The method of Claim 170, wherein said antibody, oligopeptideor organic molecule is conjugated to a growth inhibitory agent.

[0389] 177. The method of Claim 170, wherein said antibody, oligopeptideor organic molecule is conjugated to a cytotoxic agent.

[0390] 178. The method of Claim 177, wherein said cytotoxic agent isselected from the group consisting of toxins, antibiotics, radioactiveisotopes and nucleolytic enzymes.

[0391] 179. The method of Claim 177, wherein the cytotoxic agent is atoxin.

[0392] 180. The method of Claim 179, wherein the toxin is selected fromthe group consisting of maytansinoid and calicheamicin.

[0393] 181. The method of Claim 179, wherein the toxin is amaytansinoid.

[0394] 182. The method of Claim 170, wherein said antibody is producedin bacteria.

[0395] 183. The method of Claim 170, wherein said antibody is producedin CHO cells.

[0396] 184. The method of Claim 170, wherein said protein has:

[0397] (a) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120);

[0398] (b) the amino acid sequence shown in any one of FIGS. 57-112,114, 116, 118 or 120 (SEQ ID NOS:57-112, 114, 116, 118 or 120), lackingits associated signal peptide sequence;

[0399] (c) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), with its associated signal peptidesequence;

[0400] (d) an amino acid sequence of an extracellular domain of thepolypeptide shown in any one of FIGS. 57-112, 114, 116, 118 or 120 (SEQID NOS:57-112, 114, 116, 118 or 120), lacking its associated signalpeptide sequence;

[0401] (e) an amino acid sequence encoded by the nucleotide sequenceshown in any one of FIGS. 1-56, 113, 115, 117 or 119(SEQ ID NOS:1-56,113, 115, 117 or 119); or

[0402] (f) an amino acid sequence encoded by the full-length codingregion of the nucleotide sequence shown in any one of FIGS. 1-56, 113,115, 117 or 119 (SEQ ID NOS:1-56, 113, 115, 117 or 119).

[0403] Yet further embodiments of the present invention will be evidentto the skilled artisan upon a reading of the present specification.

BRIEF DESCRIPTION OF THE DRAWINGS

[0404]FIG. 1 shows a nucleotide sequence (SEQ ID NO:1) of a TAT207 cDNA,wherein SEQ ID NO:1 is a clone designated herein as “DNA67962”.

[0405]FIG. 2 shows a nucleotide sequence (SEQ ID NO:2) of a TAT177 cDNA,wherein SEQ ID NO:2 is a clone designated herein as “DNA77507”.

[0406]FIG. 3 shows a nucleotide sequence (SEQ ID NO:3) of a TAT235 cDNA,wherein SEQ ID NO:3 is a clone designated herein as “DNA87993”.

[0407]FIG. 4 shows a nucleotide sequence (SEQ ID NO:4) of a TAT234 cDNA,wherein SEQ ID NO:4 is a clone designated herein as “DNA92980”.

[0408]FIG. 5 shows a nucleotide sequence (SEQ ID NO:5) of a TAT239 cDNA,wherein SEQ ID NO:5 is a clone designated herein as “DNA96792”.

[0409]FIG. 6 shows a nucleotide sequence (SEQ ID NO:6) of a TAT193 cDNA,wherein SEQ ID NO:6 is a clone designated herein as “DNA96964”.

[0410]FIG. 7 shows a nucleotide sequence (SEQ ID NO:7) of a TAT233 cDNA,wherein SEQ ID NO:7 is a clone designated herein as “DNA105792”.

[0411]FIG. 8 shows a nucleotide sequence (SEQ ID NO:8) of a TAT226 cDNA,wherein SEQ ID NO:8 is a clone designated herein as “DNA119474”.

[0412]FIG. 9 shows a nucleotide sequence (SEQ ID NO:9) of a TAT199 cDNA,wherein SEQ ID NO:9 is a clone designated herein as “DNA142915”.

[0413] FIGS. 10A-B show a nucleotide sequence (SEQ ID NO:10) of a TAT204cDNA, wherein SEQ ID NO:10 is a clone designated herein as “DNA150491”.

[0414] FIGS. 11A-B show a nucleotide sequence (SEQ ID NO:11) of a TAT248cDNA, wherein SEQ ID NO:11 is a clone designated herein as “DNA280351”.

[0415]FIG. 12 shows a nucleotide sequence (SEQ ID NO:12) of a TAT232cDNA, wherein SEQ ID NO:12 is a clone designated herein as “DNA150648”.

[0416]FIG. 13 shows a nucleotide sequence (SEQ ID NO:13) of a TAT219cDNA, wherein SEQ ID NO:13 is a clone designated herein as “DNA172500”.

[0417]FIG. 14 shows a nucleotide sequence (SEQ ID NO:14) of a TAT224cDNA, wherein SEQ ID NO:14 is a clone designated herein as “DNA179651”.

[0418]FIG. 15 shows a nucleotide sequence (SEQ ID NO:15) of a TAT237cDNA, wherein SEQ ID NO:15 is a clone designated herein as “DNA207698”.

[0419]FIG. 16 shows a nucleotide sequence (SEQ ID NO:16) of a TAT178cDNA, wherein SEQ ID NO:16 is a clone designated herein as “DNA208551”.

[0420] FIGS. 17A-B show a nucleotide sequence (SEQ ID NO:17) of a TAT198cDNA, wherein SEQ ID NO:17 is a clone designated herein as “DNA210159”.

[0421] FIGS. 18A-B show a nucleotide sequence (SEQ ID NO:18) of a TAT194cDNA, wherein SEQ ID NO:18 is a clone designated herein as “DNA225706”.

[0422] FIGS. 19A-B show a nucleotide sequence (SEQ ID NO:19) of a TAT223cDNA, wherein SEQ ID NO:19 is a clone designated herein as “DNA225793”.

[0423]FIG. 20 shows a nucleotide sequence (SEQ ID NO:20) of a TAT196cDNA, wherein SEQ ID NO:20 is a clone designated herein as “DNA225796”.

[0424]FIG. 21 shows a nucleotide sequence (SEQ ID NO:21) of a TAT236cDNA, wherein SEQ ID NO:21 is a clone designated herein as “DNA225886”.

[0425]FIG. 22 shows a nucleotide sequence (SEQ ID NO:22) of a TAT195cDNA, wherein SEQ ID NO:22 is a clone designated herein as “DNA225943”.

[0426]FIG. 23 shows a nucleotide sequence (SEQ ID NO:23) of a TAT203cDNA, wherein SEQ ID NO:23 is a clone designated herein as “DNA226283”.

[0427] FIGS. 24A-B show a nucleotide sequence (SEQ ID NO:24) of a TAT200cDNA, wherein SEQ ID NO:24 is a clone designated herein as “DNA226589”.

[0428] FIGS. 25A-B show a nucleotide sequence (SEQ ID NO:25) of a TAT205cDNA, wherein SEQ ID NO:25 is a clone designated herein as “DNA226622”.

[0429] FIGS. 26A-B show a nucleotide sequence (SEQ ID NO:26) of a TAT185cDNA, wherein SEQ ID NO:26 is a clone designated herein as “DNA226717”.

[0430] FIGS. 27A-B show a nucleotide sequence (SEQ ID NO:27) of a TAT225cDNA, wherein SEQ ID NO:27 is a clone designated herein as “DNA227162”.

[0431]FIG. 28 shows a nucleotide sequence (SEQ ID NO:28) of a TAT247cDNA, wherein SEQ ID NO:28 is a clone designated herein as “DNA277804”.

[0432]FIG. 29 shows a nucleotide sequence (SEQ ID NO:29) of a TAT197cDNA, wherein SEQ ID NO:29 is a clone designated herein as “DNA227545”.

[0433]FIG. 30 shows a nucleotide sequence (SEQ ID NO:30) of a TAT175cDNA, wherein SEQ ID NO:30 is a clone designated herein as “DNA227611”.

[0434]FIG. 31 shows a nucleotide sequence (SEQ ID NO:31) of a TAT208cDNA, wherein SEQ ID NO:31 is a clone designated herein as “DNA261021”.

[0435]FIG. 32 shows a nucleotide sequence (SEQ ID NO:32) of a TAT174cDNA, wherein SEQ ID NO:32 is a clone designated herein as “DNA233034”.

[0436]FIG. 33 shows a nucleotide sequence (SEQ ID NO:33) of a TAT214cDNA, wherein SEQ ID NO:33 is a clone designated herein as “DNA266920”.

[0437]FIG. 34 shows a nucleotide sequence (SEQ ID NO:34) of a TAT220cDNA, wherein SEQ ID NO:34 is a clone designated herein as “DNA266921”.

[0438]FIG. 35 shows a nucleotide sequence (SEQ ID NO:35) of a TAT221cDNA, wherein SEQ ID NO:35 is a clone designated herein as “DNA266922”.

[0439]FIG. 36 shows a nucleotide sequence (SEQ ID NO:36) of a TAT201cDNA, wherein SEQ ID NO:36 is a clone designated herein as “DNA234441”.

[0440] FIGS. 37A-B show a nucleotide sequence (SEQ ID NO:37) of a TAT179cDNA, wherein SEQ ID NO:37 is a clone designated herein as “DNA234834”.

[0441]FIG. 38 shows a nucleotide sequence (SEQ ID NO:38) of a TAT216cDNA, wherein SEQ ID NO:38 is a clone designated herein as “DNA247587”.

[0442]FIG. 39 shows a nucleotide sequence (SEQ ID NO:39) of a TAT218cDNA, wherein SEQ ID NO:39 is a clone designated herein as “DNA255987”.

[0443]FIG. 40 shows a nucleotide sequence (SEQ ID NO:40) of a TAT206cDNA, wherein SEQ ID NO:40 is a clone designated herein as “DNA56041”.

[0444] FIGS. 41A-B show a nucleotide sequence (SEQ ID NO:41) of a TAT374cDNA, wherein SEQ ID NO:41 is a clone designated herein as “DNA257845”.

[0445]FIG. 42 shows a nucleotide sequence (SEQ ID NO:42) of a TAT209cDNA, wherein SEQ ID NO:42 is a clone designated herein as “DNA260655”.

[0446]FIG. 43 shows a nucleotide sequence (SEQ ID NO:43) of a TAT192cDNA, wherein SEQ ID NO:43 is a clone designated herein as “DNA260945”.

[0447]FIG. 44 shows a nucleotide sequence (SEQ ID NO:44) of a TAT180cDNA, wherein SEQ ID NO:44 is a clone designated herein as “DNA247476”.

[0448]FIG. 45 shows a nucleotide sequence (SEQ ID NO:45) of a TAT375cDNA, wherein SEQ ID NO:45 is a clone designated herein as “DNA260990”.

[0449]FIG. 46 shows a nucleotide sequence (SEQ ID NO:46) of a TAT181cDNA, wherein SEQ ID NO:46 is a clone designated herein as “DNA261001”.

[0450]FIG. 47 shows a nucleotide sequence (SEQ ID NO:47) of a TAT176cDNA, wherein SEQ ID NO:47 is a clone designated herein as “DNA261013”.

[0451]FIG. 48 shows a nucleotide sequence (SEQ ID NO:48) of a TAT184cDNA, wherein SEQ ID NO:48 is a clone designated herein as “DNA262144”.

[0452]FIG. 49 shows a nucleotide sequence (SEQ ID NO:49) of a TAT182cDNA, wherein SEQ ID NO:49 is a clone designated herein as “DNA266928”.

[0453] FIGS. 50A-B show a nucleotide sequence (SEQ ID NO:50) of a TAT213cDNA, wherein SEQ ID NO:50 is a clone designated herein as “DNA267342”.

[0454] FIGS. 51A-C show a nucleotide sequence (SEQ ID NO:51) of a TAT217cDNA, wherein SEQ ID NO:51 is a clone designated herein as “DNA267626”.

[0455]FIG. 52 shows a nucleotide sequence (SEQ ID NO:52) of a TAT222cDNA, wherein SEQ ID NO:52 is a clone designated herein as “DNA268035”.

[0456]FIG. 53 shows a nucleotide sequence (SEQ ID NO:53) of a TAT202cDNA, wherein SEQ ID NO:53 is a clone designated herein as “DNA268334”.

[0457]FIG. 54 shows a nucleotide sequence (SEQ ID NO:54) of a TAT215cDNA, wherein SEQ ID NO:54 is a clone designated herein as “DNA269238”.

[0458]FIG. 55 shows a nucleotide sequence (SEQ ID NO:55) of a TAT238cDNA, wherein SEQ ID NO:55 is a clone designated herein as “DNA272578”.

[0459]FIG. 56 shows a nucleotide sequence (SEQ ID NO:56) of a TAT212cDNA, wherein SEQ ID NO:56 is a clone designated herein as “DNA277797”.

[0460]FIG. 57 shows the amino acid sequence (SEQ ID NO:57) derived fromthe coding sequence of SEQ ID NO:1 shown in FIG. 1.

[0461]FIG. 58 shows the amino acid sequence (SEQ ID NO:58) derived fromthe coding sequence of SEQ ID NO:2 shown in FIG. 2.

[0462]FIG. 59 shows the amino acid sequence (SEQ ID NO:59) derived fromthe coding sequence of SEQ ID NO:3 shown in FIG. 3.

[0463]FIG. 60 shows the amino acid sequence (SEQ ID NO:60) derived fromthe coding sequence of SEQ ID NO:4 shown in FIG. 4.

[0464]FIG. 61 shows the amino acid sequence (SEQ ID NO:61) derived fromthe coding sequence of SEQ ID NO:5 shown in FIG. 5.

[0465]FIG. 62 shows the amino acid sequence (SEQ ID NO:62) derived fromthe coding sequence of SEQ ID NO:6 shown in FIG. 6.

[0466]FIG. 63 shows the amino acid sequence (SEQ ID NO:63) derived fromthe coding sequence of SEQ ID NO:7 shown in FIG. 7.

[0467]FIG. 64 shows the amino acid sequence (SEQ ID NO:64) derived fromthe coding sequence of SEQ ID NO:8 shown in FIG. 8.

[0468]FIG. 65 shows the amino acid sequence (SEQ ID NO:65) derived fromthe coding sequence of SEQ ID NO:9 shown in FIG. 9.

[0469]FIG. 66 shows the amino acid sequence (SEQ ID NO:66) derived fromthe coding sequence of SEQ ID NO:10 shown in FIGS. 10A-B.

[0470]FIG. 67 shows the amino acid sequence (SEQ ID NO:67) derived fromthe coding sequence of SEQ ID NO:11 shown in FIGS. 11A-B.

[0471]FIG. 68 shows the amino acid sequence (SEQ ID NO:68) derived fromthe coding sequence of SEQ ID NO:12 shown in FIG. 12.

[0472]FIG. 69 shows the amino acid sequence (SEQ ID NO:69) derived fromthe coding sequence of SEQ ID NO:13 shown in FIG. 13.

[0473]FIG. 70 shows the amino acid sequence (SEQ ID NO:70) derived fromthe coding sequence of SEQ ID NO:14 shown in FIG. 14.

[0474]FIG. 71 shows the amino acid sequence (SEQ ID NO:71) derived fromthe coding sequence of SEQ ID NO:15 shown in FIG. 15.

[0475]FIG. 72 shows the amino acid sequence (SEQ ID NO:72) derived fromthe coding sequence of SEQ ID NO:16 shown in FIG. 16.

[0476]FIG. 73 shows the amino acid sequence (SEQ ID NO:73) derived fromthe coding sequence of SEQ ID NO:17 shown in FIGS. 17A-B.

[0477]FIG. 74 shows the amino acid sequence (SEQ ID NO:74) derived fromthe coding sequence of SEQ ID NO:18 shown in FIGS. 18A-B.

[0478]FIG. 75 shows the amino acid sequence (SEQ ID NO:75) derived fromthe coding sequence of SEQ ID NO:19 shown in FIGS. 19A-B.

[0479]FIG. 76 shows the amino acid sequence (SEQ ID NO:76) derived fromthe coding sequence of SEQ ID NO:20 shown in FIG. 20.

[0480]FIG. 77 shows the amino acid sequence (SEQ ID NO:77) derived fromthe coding sequence of SEQ ID NO:21 shown in FIG. 21.

[0481]FIG. 78 shows the amino acid sequence (SEQ ID NO:78) derived fromthe coding sequence of SEQ ID NO:22 shown in FIG. 22.

[0482]FIG. 79 shows the amino acid sequence (SEQ ID NO:79) derived fromthe coding sequence of SEQ ID NO:23 shown in FIG. 23.

[0483]FIG. 80 shows the amino acid sequence (SEQ ID NO:80) derived fromthe coding sequence of SEQ ID NO:24 shown in FIGS. 24A-B.

[0484]FIG. 81 shows the amino acid sequence (SEQ ID NO:81) derived fromthe coding sequence of SEQ ID NO:25 shown in FIGS. 25A-B.

[0485]FIG. 82 shows the amino acid sequence (SEQ ID NO:82) derived fromthe coding sequence of SEQ ID NO:26 shown in FIGS. 26A-B.

[0486]FIG. 83 shows the amino acid sequence (SEQ ID NO:83) derived fromthe coding sequence of SEQ ID NO:27 shown in FIGS. 27A-B.

[0487]FIG. 84 shows the amino acid sequence (SEQ ID NO:84) derived fromthe coding sequence of SEQ ID NO:28 shown in FIG. 28.

[0488]FIG. 85 shows the amino acid sequence (SEQ ID NO:85) derived fromthe coding sequence of SEQ ID NO:29 shown in FIG. 29.

[0489]FIG. 86 shows the amino acid sequence (SEQ ID NO:86) derived fromthe coding sequence of SEQ ID NO:30 shown in FIG. 30.

[0490]FIG. 87 shows the amino acid sequence (SEQ ID NO:87) derived fromthe coding sequence of SEQ ID NO:31 shown in FIG. 31.

[0491]FIG. 88 shows the amino acid sequence (SEQ ID NO:88) derived fromthe coding sequence of SEQ ID NO:32 shown in FIG. 32.

[0492]FIG. 89 shows the amino acid sequence (SEQ ID NO:89) derived fromthe coding sequence of SEQ ID NO:33 shown in FIG. 33.

[0493]FIG. 90 shows the amino acid sequence (SEQ ID NO:90) derived fromthe coding sequence of SEQ ID NO:34 shown in FIG. 34.

[0494]FIG. 91 shows the amino acid sequence (SEQ ID NO:91) derived fromthe coding sequence of SEQ ID NO:35 shown in FIG. 35.

[0495]FIG. 92 shows the amino acid sequence (SEQ ID NO:92) derived fromthe coding sequence of SEQ ID NO:36 shown in FIG. 36.

[0496]FIG. 93 shows the amino acid sequence (SEQ ID NO:93) derived fromthe coding sequence of SEQ ID NO:37 shown in FIGS. 37A-B.

[0497]FIG. 94 shows the amino acid sequence (SEQ ID NO:94) derived fromthe coding sequence of SEQ ID NO:38 shown in FIG. 38.

[0498]FIG. 95 shows the amino acid sequence (SEQ ID NO:95) derived fromthe coding sequence of SEQ ID NO:39 shown in FIG. 39.

[0499]FIG. 96 shows the amino acid sequence (SEQ ID NO:96) derived fromthe coding sequence of SEQ ID NO:40 shown in FIG. 40.

[0500]FIG. 97 shows the amino acid sequence (SEQ ID NO:97) derived fromthe coding sequence of SEQ ID NO:41 shown in FIGS. 41A-B.

[0501]FIG. 98 shows the amino acid sequence (SEQ ID NO:98) derived fromthe coding sequence of SEQ ID NO:42 shown in FIG. 42.

[0502]FIG. 99 shows the amino acid sequence (SEQ ID NO:99) derived fromthe coding sequence of SEQ ID NO:43 shown in FIG. 43.

[0503]FIG. 100 shows the amino acid sequence (SEQ ID NO:100) derivedfrom the coding sequence of SEQ ID NO:44 shown in FIG. 44.

[0504]FIG. 101 shows the amino acid sequence (SEQ ID NO:101) derivedfrom the coding sequence of SEQ ID NO:45 shown in FIG. 45.

[0505]FIG. 102 shows the amino acid sequence (SEQ ID NO:102) derivedfrom the coding sequence of SEQ ID NO:46 shown in FIG. 46.

[0506]FIG. 103 shows the amino acid sequence (SEQ ID NO:103) derivedfrom the coding sequence of SEQ ID NO:47 shown in FIG. 47.

[0507]FIG. 104 shows the amino acid sequence (SEQ ID NO:104) derivedfrom the coding sequence of SEQ ID NO:48 shown in FIG. 48.

[0508]FIG. 105 shows the amino acid sequence (SEQ ID NO:105) derivedfrom the coding sequence of SEQ ID NO:49 shown in FIG. 49.

[0509]FIG. 106 shows the amino acid sequence (SEQ ID NO:106) derivedfrom the coding sequence of SEQ ID NO:50 shown in FIGS. 50A-B.

[0510] FIGS. 107A-B show the amino acid sequence (SEQ ID NO:107) derivedfrom the coding sequence of SEQ ID NO:51 shown in FIGS. 51A-C.

[0511]FIG. 108 shows the amino acid sequence (SEQ ID NO:108) derivedfrom the coding sequence of SEQ ID NO:52 shown in FIG. 52.

[0512]FIG. 109 shows the amino acid sequence (SEQ ID NO:109) derivedfrom the coding sequence of SEQ ID NO:53 shown in FIG. 53.

[0513]FIG. 110 shows the amino acid sequence (SEQ ID NO:110) derivedfrom the coding sequence of SEQ ID NO:54 shown in FIG. 54.

[0514]FIG. 111 shows the amino acid sequence (SEQ ID NO:111) derivedfrom the coding sequence of SEQ ID NO:55 shown in FIG. 55.

[0515]FIG. 112 shows the amino acid sequence (SEQ ID NO:112) derivedfrom the coding sequence of SEQ ID NO:56 shown in FIG. 56.

[0516]FIG. 113 shows a nucleotide sequence (SEQ ID NO:113) of a TAT376cDNA, wherein SEQ ID NO:113 is a clone designated herein as “DNA304853”.

[0517]FIG. 114 shows the amino acid sequence (SEQ ID NO:114) derivedfrom the coding sequence of SEQ ID NO:113 shown in FIG. 113.

[0518]FIG. 115 shows a nucleotide sequence (SEQ ID NO:115) of a TAT377cDNA, wherein SEQ ID NO:115 is a clone designated herein as “DNA304854”.

[0519]FIG. 116 shows the amino acid sequence (SEQ ID NO:116) derivedfrom the coding sequence of SEQ ID NO:115 shown in FIG. 115.

[0520]FIG. 117 shows a nucleotide sequence (SEQ ID NO:117) of a TAT378cDNA, wherein SEQ ID NO:117 is a clone designated herein as “DNA304855”.

[0521]FIG. 118 shows the amino acid sequence (SEQ ID NO:118) derivedfrom the coding sequence of SEQ ID NO:117 shown in FIG. 117.

[0522] FIGS. 119A-B show a nucleotide sequence (SEQ ID NO:119) of aTAT379 cDNA, wherein SEQ ID NO:119 is a clone designated herein as“DNA287971”.

[0523]FIG. 120 shows the amino acid sequence (SEQ ID NO:120) derivedfrom the coding sequence of SEQ ID NO:119 shown in FIGS. 119A-B.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0524] I. Definitions

[0525] The terms “TAT polypeptide” and “TAT” as used herein and whenimmediately followed by a numerical designation, refer to variouspolypeptides, wherein the complete designation (i.e.,TAT/number) refersto specific polypeptide sequences as described herein. The terms“TAT/number polypeptide” and “TAT/number” wherein the term “number” isprovided as an actual numerical designation as used herein encompassnative sequence polypeptides, polypeptide variants and fragments ofnative sequence polypeptides and polypeptide variants (which are furtherdefined herein). The TAT polypeptides described herein may be isolatedfrom a variety of sources, such as from human tissue types or fromanother source, or prepared by recombinant or synthetic methods. Theterm “TAT polypeptide” refers to each individual TAT/number polypeptidedisclosed herein. All disclosures in this specification which refer tothe “TAT polypeptide” refer to each of the polypeptides individually aswell as jointly. For example, descriptions of the preparation of,purification of, derivation of, formation of antibodies to or against,formation of TAT binding oligopeptides to or against, formation of TATbinding organic molecules to or against, administration of, compositionscontaining, treatment of a disease with, etc., pertain to eachpolypeptide of the invention individually. The term “TAT polypeptide”also includes variants of the TAT/number polypeptides disclosed herein.

[0526] A “native sequence TAT polypeptide” comprises a polypeptidehaving the same amino acid sequence as the corresponding TAT polypeptidederived from nature. Such native sequence TAT polypeptides can beisolated from nature or can be produced by recombinant or syntheticmeans. The term “native sequence TAT polypeptide” specificallyencompasses naturally-occurring truncated or secreted forms of thespecific TAT polypeptide (e.g., an extracellular domain sequence),naturally-occurring variant forms (e.g., alternatively spliced forms)and naturally-occurring allelic variants of the polypeptide. In certainembodiments of the invention, the native sequence TAT polypeptidesdisclosed herein are mature or full-length native sequence polypeptidescomprising the full-length amino acids sequences shown in theaccompanying figures. Start and stop codons (if indicated) are shown inbold font and underlined in the figures. Nucleic acid residues indicatedas “N” in the accompanying figures are any nucleic acid residue.However, while the TAT polypeptides disclosed in the accompanyingfigures are shown to begin with methionine residues designated herein asamino acid position 1 in the figures, it is conceivable and possiblethat other methionine residues located either upstream or downstreamfrom the amino acid position 1 in the figures may be employed as thestarting amino acid residue for the TAT polypeptides.

[0527] The TAT polypeptide “extracellular domain” or “ECD” refers to aform of the TAT polypeptide which is essentially free of thetransmembrane and cytoplasmic domains. Ordinarily, a TAT polypeptide ECDwill have less than 1% of such transmembrane and/or cytoplasmic domainsand preferably, will have less than 0.5% of such domains. It will beunderstood that any transmembrane domains identified for theTATpolypeptides of the present invention are identified pursuant tocriteria routinely employed in the art for identifying that type ofhydrophobic domain. The exact boundaries of a transmembrane domain mayvary but most likely by no more than about 5 amino acids at either endof the domain as initially identified herein. Optionally, therefore, anextracellular domain of a TAT polypeptide may contain from about 5 orfewer amino acids on either side of the transmembranedomain/extracellular domain boundary as identified in the Examples orspecification and such polypeptides, with or without the associatedsignal peptide, and nucleic acid encoding them, are contemplated by thepresent invention.

[0528] The approximate location of the “signal peptides” of the variousTAT polypeptides disclosed herein may be shown in the presentspecification and/or the accompanying figures. It is noted, however,that the C-terminal boundary of a signal peptide may vary, but mostlikely by no more than about 5 amino acids on either side of the signalpeptide C-terminal boundary as initially identified herein, wherein theC-terminal boundary of the signal peptide may be identified pursuant tocriteria routinely employed in the art for identifying that type ofamino acid sequence element (e.g., Nielsen et al., Prot. En. 10:1-6(1997) and von Heinje et al., Nucl. Acids. Res. 14:4683-4690 (1986)).Moreover, it is also recognized that, in some cases, cleavage of asignal sequence from a secreted polypeptide is not entirely uniform,resulting in more than one secreted species. These mature polypeptides,where the signal peptide is cleaved within no more than about 5 aminoacids on either side of the C-terminal boundary of the signal peptide asidentified herein, and the polynucleotides encoding them, arecontemplated by the present invention.

[0529] “TAT polypeptide variant” means a TAT polypeptide, preferably anactive TAT polypeptide, as defined herein having at least about 80%amino acid sequence identity with a full-length native sequence TATpolypeptide sequence as disclosed herein, a TAT polypeptide sequencelacking the signal peptide as disclosed herein, an extracellular domainof a TAT polypeptide, with or without the signal peptide, as disclosedherein or any other fragment of a full-length TAT polypeptide sequenceas disclosed herein (such as those encoded by a nucleic acid thatrepresents only a portion of the complete coding sequence for afull-length TAT polypeptide). Such TAT polypeptide variants include, forinstance, TAT polypeptides wherein one or more amino acid residues areadded, or deleted, at the N- or C-terminus of the full-length nativeamino acid sequence. Ordinarily, a TAT polypeptide variant will have atleast about 80% amino acid sequence identity, alternatively at leastabout 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98, or 99% amino acid sequence identity, to afull-length native sequence TAT polypeptide sequence as disclosedherein, a TAT polypeptide sequence lacking the signal peptide asdisclosed herein, an extracellular domain of a TAT polypeptide, with orwithout the signal peptide, as disclosed herein or any otherspecifically defined fragment of a full-length TAT polypeptide sequenceas disclosed herein. Ordinarily, TAT variant polypeptides are at leastabout 10 amino acids in length, alternatively at least about 20, 30, 40,50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190,200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330,340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470,480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600 aminoacids in length, or more. Optionally, TAT variant polypeptides will haveno more than one conservative amino acid substitution as compared to thenative TAT polypeptide sequence, alternatively no more than 2, 3, 4, 5,6, 7, 8, 9, or 10 conservative amino acid substitution as compared tothe native TAT polypeptide sequence.

[0530] “Percent (%) amino acid sequence identity” with respect to theTAT polypeptide sequences identified herein is defined as the percentageof amino acid residues in a candidate sequence that are identical withthe amino acid residues in the specific TAT polypeptide sequence, afteraligning the sequences and introducing gaps, if necessary, to achievethe maximum percent sequence identity, and not considering anyconservative substitutions as part of the sequence identity. Alignmentfor purposes of determining percent amino acid sequence identity can beachieved in various ways that are within the skill in the art, forinstance, using publicly available computer software such as BLAST,BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the artcan determine appropriate parameters for measuring alignment, includingany algorithms needed to achieve maximal alignment over the full lengthof the sequences being compared. For purposes herein, however, % aminoacid sequence identity values are generated using the sequencecomparison computer program ALIGN-2, wherein the complete source codefor the ALIGN-2 program is provided in Table 1 below. The ALIGN-2sequence comparison computer program was authored by Genentech, Inc. andthe source code shown in Table 1 below has been filed with userdocumentation in the U.S. Copyright Office, Washington D.C., 20559,where it is registered under U.S. Copyright Registration No. TXU510087.The ALIGN-2 program is publicly available through Genentech, Inc., SouthSan Francisco, Calif. or may be compiled from the source code providedin Table 1 below. The ALIGN-2 program should be compiled for use on aUNIX operating system, preferably digital UNIX V4.0D. All sequencecomparison parameters are set by the ALIGN-2 program and do not vary.

[0531] In situations where ALIGN-2 is employed for amino acid sequencecomparisons, the % amino acid sequence identity of a given amino acidsequence A to, with, or against a given amino acid sequence B (which canalternatively be phrased as a given amino acid sequence A that has orcomprises a certain % amino acid sequence identity to, with, or againsta given amino acid sequence B) is calculated as follows:

100 times the fraction X/Y

[0532] where X is the number of amino acid residues scored as identicalmatches by the sequence alignment program ALIGN-2 in that program'salignment of A and B, and where Y is the total number of amino acidresidues in B. It will be appreciated that where the length of aminoacid sequence A is not equal to the length of amino acid sequence B, the% amino acid sequence identity of A to B will not equal the % amino acidsequence identity of B to A. As examples of % amino acid sequenceidentity calculations using this method, Tables 2 and 3 demonstrate howto calculate the % amino acid sequence identity of the amino acidsequence designated “Comparison Protein” to the amino acid sequencedesignated “TAT”, wherein “TAT” represents the amino acid sequence of ahypothetical TAT polypeptide of interest, “Comparison Protein”represents the amino acid sequence of a polypeptide against which the“TAT” polypeptide of interest is being compared, and “X, “Y” and “Z”each represent different hypothetical amino acid residues. Unlessspecifically stated otherwise, all % amino acid sequence identity valuesused herein are obtained as described in the immediately precedingparagraph using the ALIGN-2 computer program.

[0533] “TAT variant polynucleotide” or “TAT variant nucleic acidsequence” means a nucleic acid molecule which encodes a TAT polypeptide,preferably an active TAT polypeptide, as defined herein and which has atleast about 80% nucleic acid sequence identity with a nucleotide acidsequence encoding a full-length native sequence TAT polypeptide sequenceas disclosed herein, a full-length native sequence TAT polypeptidesequence lacking the signal peptide as disclosed herein, anextracellular domain of a TAT polypeptide, with or without the signalpeptide, as disclosed herein or any other fragment of a full-length TATpolypeptide sequence as disclosed herein (such as those encoded by anucleic acid that represents only a portion of the complete codingsequence for a full-length TAT polypeptide). Ordinarily, a TAT variantpolynucleotide will have at least about 80% nucleic acid sequenceidentity, alternatively at least about 81%, 82%, 83%, 84%, 85%, 86%,87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%nucleic acid sequence identity with a nucleic acid sequence encoding afull-length native sequence TAT polypeptide sequence as disclosedherein, a full-length native sequence TAT polypeptide sequence lackingthe signal peptide as disclosed herein, an extracellular domain of a TATpolypeptide, with or without the signal sequence, as disclosed herein orany other fragment of a full-length TAT polypeptide sequence asdisclosed herein. Variants do not encompass the native nucleotidesequence.

[0534] Ordinarily, TAT variant polynucleotides are at least about 5nucleotides in length, alternatively at least about 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110,115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180,185, 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300,310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440,450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580,590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720,730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860,870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, or 1000nucleotides in length, wherein in this context the term “about” meansthe referenced nucleotide sequence length plus or minus 10% of thatreferenced length.

[0535] “Percent (%) nucleic acid sequence identity” with respect toTAT-encoding nucleic acid sequences identified herein is defined as thepercentage of nucleotides in a candidate sequence that are identicalwith the nucleotides in the TAT nucleic acid sequence of interest, afteraligning the sequences and introducing gaps, if necessary, to achievethe maximum percent sequence identity. Alignment for purposes ofdetermining percent nucleic acid sequence identity can be achieved invarious ways that are within the skill in the art, for instance, usingpublicly available computer software such as BLAST, BLAST-2, ALIGN orMegalign (DNASTAR) software. For purposes herein, however, % nucleicacid sequence identity values are generated using the sequencecomparison computer program ALIGN-2, wherein the complete source codefor the ALIGN-2 program is provided in Table 1 below. The ALIGN-2sequence comparison computer program was authored by Genentech, Inc. andthe source code shown in Table 1 below has been filed with userdocumentation in the U.S. Copyright Office, Washington D.C., 20559,where it is registered under U.S. Copyright Registration No. TXU510087.The ALIGN-2 program is publicly available through Genentech, Inc., SouthSan Francisco, Calif. or may be compiled from the source code providedin Table 1 below. The ALIGN-2 program should be compiled for use on aUNIX operating system, preferably digital UNIX V4.0D. All sequencecomparison parameters are set by the ALIGN-2 program and do not vary.

[0536] In situations where ALIGN-2 is employed for nucleic acid sequencecomparisons, the % nucleic acid sequence identity of a given nucleicacid sequence C to, with, or against a given nucleic acid sequence D(which can alternatively be phrased as a given nucleic acid sequence Cthat has or comprises a certain % nucleic acid sequence identity to,with, or against a given nucleic acid sequence D) is calculated asfollows:

100 times the fraction W/Z

[0537] where W is the number of nucleotides scored as identical matchesby the sequence alignment program ALIGN-2 in that program's alignment ofC and D, and where Z is the total number of nucleotides in D. It will beappreciated that where the length of nucleic acid sequence C is notequal to the length of nucleic acid sequence D, the % nucleic acidsequence identity of C to D will not equal the % nucleic acid sequenceidentity of D to C. As examples of % nucleic acid sequence identitycalculations, Tables 4 and 5, demonstrate how to calculate the % nucleicacid sequence identity of the nucleic acid sequence designated“Comparison DNA” to the nucleic acid sequence designated “TAT-DNA”,wherein “TAT-DNA” represents a hypothetical TAT-encoding nucleic acidsequence of interest, “Comparison DNA” represents the nucleotidesequence of a nucleic acid molecule against which the “TAT-DNA” nucleicacid molecule of interest is being compared, and “N”, “L” and “V” eachrepresent different hypothetical nucleotides. Unless specifically statedotherwise, all % nucleic acid sequence identity values used herein areobtained as described in the immediately preceding paragraph using theALIGN-2 computer program.

[0538] In other embodiments, TAT variant polynucleotides are nucleicacid molecules that encode a TAT polypeptide and which are capable ofhybridizing, preferably under stringent hybridization and washconditions, to nucleotide sequences encoding a full-length TATpolypeptide as disclosed herein. TAT variant polypeptides may be thosethat are encoded by a TAT variant polynucleotide.

[0539] The term “full-length coding region” when used in reference to anucleic acid encoding a TAT polypeptide refers to the sequence ofnucleotides which encode the full-length TAT polypeptide of theinvention (which is often shown between start and stop codons, inclusivethereof, in the accompanying figures). The term “full-length codingregion” when used in reference to an ATCC deposited nucleic acid refersto the TAT polypeptide-encoding portion of the cDNA that is insertedinto the vector deposited with the ATCC (which is often shown betweenstart and stop codons, inclusive thereof, in the accompanying figures).

[0540] “Isolated,” when used to describe the various TAT polypeptidesdisclosed herein, means polypeptide that has been identified andseparated and/or recovered from a component of its natural environment.Contaminant components of its natural environment are materials thatwould typically interfere with diagnostic or therapeutic uses for thepolypeptide, and may include enzymes, hormones, and other proteinaceousor non-proteinaceous solutes. In preferred embodiments, the polypeptidewill be purified (1) to a degree sufficient to obtain at least 15residues of N-terminal or internal amino acid sequence by use of aspinning cup sequenator, or (2) to homogeneity by SDS-PAGE undernon-reducing or reducing conditions using Coomassie blue or, preferably,silver stain. Isolated polypeptide includes polypeptide in situ withinrecombinant cells, since at least one component of the TAT polypeptidenatural environment will not be present. Ordinarily, however, isolatedpolypeptide will be prepared by at least one purification step.

[0541] An “isolated” TAT polypeptide-encoding nucleic acid or otherpolypeptide-encoding nucleic acid is a nucleic acid molecule that isidentified and separated from at least one contaminant nucleic acidmolecule with which it is ordinarily associated in the natural source ofthe polypeptide-encoding nucleic acid. An isolated polypeptide-encodingnucleic acid molecule is other than in the form or setting in which itis found in nature. Isolated polypeptide-encoding nucleic acid moleculestherefore are distinguished from the specific polypeptide-encodingnucleic acid molecule as it exists in natural cells. However, anisolated polypeptide-encoding nucleic acid molecule includespolypeptide-encoding nucleic acid molecules contained in cells thatordinarily express the polypeptide where, for example, the nucleic acidmolecule is in a chromosomal location different from that of naturalcells.

[0542] The term “control sequences” refers to DNA sequences necessaryfor the expression of an operably linked coding sequence in a particularhost organism. The control sequences that are suitable for prokaryotes,for example, include a promoter, optionally an operator sequence, and aribosome binding site. Eukaryotic cells are known to utilize promoters,polyadenylation signals, and enhancers.

[0543] Nucleic acid is “operably linked” when it is placed into afunctional relationship with another nucleic acid sequence. For example,DNA for a presequence or secretory leader is operably linked to DNA fora polypeptide if it is expressed as a preprotein that participates inthe secretion of the polypeptide; a promoter or enhancer is operablylinked to a coding sequence if it affects the transcription of thesequence; or a ribosome binding site is operably linked to a codingsequence if it is positioned so as to facilitate translation. Generally,“operably linked” means that the DNA sequences being linked arecontiguous, and, in the case of a secretory leader, contiguous and inreading phase. However, enhancers do not have to be contiguous. Linkingis accomplished by ligation at convenient restriction sites. If suchsites do not exist, the synthetic oligonucleotide adaptors or linkersare used in accordance with conventional practice.

[0544] “Stringency” of hybridization reactions is readily determinableby one of ordinary skill in the art, and generally is an empiricalcalculation dependent upon probe length, washing temperature, and saltconcentration. In general, longer probes require higher temperatures forproper annealing, while shorter probes need lower temperatures.Hybridization generally depends on the ability of denatured DNA toreanneal when complementary strands are present in an environment belowtheir melting temperature. The higher the degree of desired homologybetween the probe and hybridizable sequence, the higher the relativetemperature which can be used. As a result, it follows that higherrelative temperatures would tend to make the reaction conditions morestringent, while lower temperatures less so. For additional details andexplanation of stringency of hybridization reactions, see Ausubel etal., Current Protocols in Molecular Biology, Wiley IntersciencePublishers, (1995).

[0545] “Stringent conditions” or “high stringency conditions”, asdefined herein, may be identified by those that: (1) employ low ionicstrength and high temperature for washing, for example 0.015 M sodiumchloride/0.0015 M sodium citrate/0.1% sodium dodecyl sulfate at 50° C.;(2) employ during hybridization a denaturing agent, such as formamide,for example, 50% (v/v) formamide with 0.1% bovine serum albumin/0.1%Ficoll/0.1% polyvinylpyrrolidone/50 mM sodium phosphate buffer at pH 6.5with 750 mM sodium chloride, 75 mM sodium citrate at 42° C.; or (3)overnight hybridization in a solution that employs 50% formamide, 5×SSC(0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8),0.1% sodium pyrophosphate, 5× Denhardt's solution, sonicated salmonsperm DNA (50 μg/nl), 0.1% SDS, and 10% dextran sulfate at 42° C., witha 10 minute wash at 42° C. in 0.2×SSC (sodium chloride/sodium citrate)followed by a 10 minute high-stringency wash consisting of 0.1×SSCcontaining EDTA at 55° C.

[0546] “Moderately stringent conditions” may be identified as describedby Sambrook et al., Molecular Cloning: A Laboratory Manual, New York:Cold Spring Harbor Press, 1989, and include the use of washing solutionand hybridization conditions (e.g., temperature, ionic strength and %SDS) less stringent that those described above. An example of moderatelystringent conditions is overnight incubation at 37° C. in a solutioncomprising:20% formamide, 5×SSC (150 mM NaCl, 15 mM trisodium citrate),50 mM sodium phosphate (pH 7.6), 5× Denhardt's solution, 10% dextransulfate, and 20 mg/ml denatured sheared salmon sperm DNA, followed bywashing the filters in 1×SSC at about 37-50° C. The skilled artisan willrecognize how to adjust the temperature, ionic strength, etc. asnecessary to accommodate factors such as probe length and the like.

[0547] The term “epitope tagged” when used herein refers to a chimericpolypeptide comprising a TAT polypeptide or anti-TAT antibody fused to a“tag polypeptide”. The tag polypeptide has enough residues to provide anepitope against which an antibody can be made, yet is short enough suchthat it does not interfere with activity of the polypeptide to which itis fused. The tag polypeptide preferably also is fairly unique so thatthe antibody does not substantially cross-react with other epitopes.Suitable tag polypeptides generally have at least six amino acidresidues and usually between about 8 and 50 amino acid residues(preferably, between about 10 and 20 amino acid residues).

[0548] “Active” or “activity” for the purposes herein refers to form(s)of a TAT polypeptide which retain a biological and/or an immunologicalactivity of native or naturally-occurring TAT, wherein “biological”activity refers to a biological function (either inhibitory orstimulatory) caused by a native or naturally-occurring TAT other thanthe ability to induce the production of an antibody against an antigenicepitope possessed by a native or naturally-occurring TAT and an“immunological” activity refers to the ability to induce the productionof an antibody against an antigenic epitope possessed by a native ornaturally-occurring TAT.

[0549] The term “antagonist” is used in the broadest sense, and includesany molecule that partially or fully blocks, inhibits, or neutralizes abiological activity of a native TAT polypeptide disclosed herein. In asimilar manner, the term “agonist” is used in the broadest sense andincludes any molecule that mimics a biological activity of a native TATpolypeptide disclosed herein. Suitable agonist or antagonist moleculesspecifically include agonist or antagonist antibodies or antibodyfragments, fragments or amino acid sequence variants of native TATpolypeptides, peptides, antisense oligonucleotides, small organicmolecules, etc. Methods for identifying agonists or antagonists of a TATpolypeptide may comprise contacting a TAT polypeptide with a candidateagonist or antagonist molecule and measuring a detectable change in oneor more biological activities normally associated with the TATpolypeptide.

[0550] “Treating” or “treatment” or “alleviation” refers to boththerapeutic treatment and prophylactic or preventative measures, whereinthe object is to prevent or slow down (lessen) the targeted pathologiccondition or disorder. Those in need of treatment include those alreadywith the disorder as well as those prone to have the disorder or thosein whom the disorder is to be prevented. A subject or mammal issuccessfully “treated” for a TAT polypeptide-expressing cancer if, afterreceiving a therapeutic amount of an anti-TAT antibody, TAT bindingoligopeptide or TAT binding organic molecule according to the methods ofthe present invention, the patient shows observable and/or measurablereduction in or absence of one or more of the following: reduction inthe number of cancer cells or absence of the cancer cells; reduction inthe tumor size; inhibition (i.e., slow to some extent and preferablystop) of cancer cell infiltration into peripheral organs including thespread of cancer into soft tissue and bone; inhibition (i.e., slow tosome extent and preferably stop) of tumor metastasis; inhibition, tosome extent, of tumor growth; and/or relief to some extent, one or moreof the symptoms associated with the specific cancer; reduced morbidityand mortality, and improvement in quality of life issues. To the extentthe anti-TAT antibody or TAT binding oligopeptide may prevent growthand/or kill existing cancer cells, it may be cytostatic and/orcytotoxic. Reduction of these signs or symptoms may also be felt by thepatient.

[0551] The above parameters for assessing successful treatment andimprovement in the disease are readily measurable by routine proceduresfamiliar to a physician. For cancer therapy, efficacy can be measured,for example, by assessing the time to disease progression (TTP) and/ordetermining the response rate (RR). Metastasis can be determined bystaging tests and by bone scan and tests for calcium level and otherenzymes to determine spread to the bone. CT scans can also be done tolook for spread to the pelvis and lymph nodes in the area. Chest X-raysand measurement of liver enzyme levels by known methods are used to lookfor metastasis to the lungs and liver, respectively. Other routinemethods for monitoring the disease include transrectal ultrasonography(TRUS) and transrectal needle biopsy (TRNB).

[0552] For bladder cancer, which is a more localized cancer, methods todetermine progress of disease include urinary cytologic evaluation bycystoscopy, monitoring for presence of blood in the urine, visualizationof the urothelial tract by sonography or an intravenous pyelogram,computed tomography (CT) and magnetic resonance imaging (MRI). Thepresence of distant metastases can be assessed by CT of the abdomen,chest x-rays, or radionuclide imaging of the skeleton.

[0553] “Chronic” administration refers to administration of the agent(s)in a continuous mode as opposed to an acute mode, so as to maintain theinitial therapeutic effect (activity) for an extended period of time.“Intermittent” administration is treatment that is not consecutivelydone without interruption, but rather is cyclic in nature.

[0554] “Mammal” for purposes of the treatment of, alleviating thesymptoms of or diagnosis of a cancer refers to any animal classified asa mammal, including humans, domestic and farm animals, and zoo, sports,or pet animals, such as dogs, cats, cattle, horses, sheep, pigs, goats,rabbits, etc. Preferably, the mammal is human.

[0555] Administration “in combination with” one or more furthertherapeutic agents includes simultaneous (concurrent) and consecutiveadministration in any order.

[0556] “Carriers” as used herein include pharmaceutically acceptablecarriers, excipients, or stabilizers which are nontoxic to the cell ormammal being exposed thereto at the dosages and concentrations employed.Often the physiologically acceptable carrier is an aqueous pH bufferedsolution. Examples of physiologically acceptable carriers includebuffers such as phosphate, citrate, and other organic acids;antioxidants including ascorbic acid; low molecular weight (less thanabout 10 residues) polypeptide; proteins, such as serum albumin,gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, arginine or lysine; monosaccharides, disaccharides, andother carbohydrates including glucose, mannose, or dextrins; chelatingagents such as EDTA; sugar alcohols such as mannitol or sorbitol;salt-forming counterions such as sodium; and/or nonionic surfactantssuch as TWEEN®, polyethylene glycol (PEG), and PLURONICS®.

[0557] By “solid phase” or “solid support” is meant a non-aqueous matrixto which an antibody, TAT binding oligopeptide or TAT binding organicmolecule of the present invention can adhere or attach. Examples ofsolid phases encompassed herein include those formed partially orentirely of glass (e.g., controlled pore glass), polysaccharides (e.g.,agarose), polyacrylamides, polystyrene, polyvinyl alcohol and silicones.In certain embodiments, depending on the context, the solid phase cancomprise the well of an assay plate; in others it is a purificationcolumn (e.g., an affinity chromatography column). This term alsoincludes a discontinuous solid phase of discrete particles, such asthose described in U.S. Pat. No. 4,275,149.

[0558] A “liposome” is a small vesicle composed of various types oflipids, phospholipids and/or surfactant which is useful for delivery ofa drug (such as a TAT polypeptide, an antibody thereto or a TAT bindingoligopeptide) to a mammal. The components of the liposome are commonlyarranged in a bilayer formation, similar to the lipid arrangement ofbiological membranes.

[0559] A “small” molecule or “small” organic molecule is defined hereinto have a molecular weight below about 500 Daltons.

[0560] An “effective amount” of a polypeptide, antibody, TAT bindingoligopeptide, TAT binding organic molecule or an agonist or antagonistthereof as disclosed herein is an amount sufficient to carry out aspecifically stated purpose. An “effective amount” may be determinedempirically and in a routine manner, in relation to the stated purpose.

[0561] The term “therapeutically effective amount” refers to an amountof an antibody, polypeptide, TAT binding oligopeptide, TAT bindingorganic molecule or other drug effective to “treat” a disease ordisorder in a subject or mammal. In the case of cancer, thetherapeutically effective amount of the drug may reduce the number ofcancer cells; reduce the tumor size; inhibit (i.e., slow to some extentand preferably stop) cancer cell infiltration into peripheral organs;inhibit (i.e., slow to some extent and preferably stop) tumormetastasis; inhibit, to some extent, tumor growth; and/or relieve tosome extent one or more of the symptoms associated with the cancer. Seethe definition herein of “treating”. To the extent the drug may preventgrowth and/or kill existing cancer cells, it may be cytostatic and/orcytotoxic.

[0562] A “growth inhibitory amount” of an anti-TAT antibody, TATpolypeptide, TAT binding oligopeptide or TAT binding organic molecule isan amount capable of inhibiting the growth of a cell, especially tumor,e.g., cancer cell, either in vitro or in vivo. A “growth inhibitoryamount” of an anti-TAT antibody, TAT polypeptide, TAT bindingoligopeptide or TAT binding organic molecule for purposes of inhibitingneoplastic cell growth may be determined empirically and in a routinemanner.

[0563] A “cytotoxic amount” of an anti-TAT antibody, TAT polypeptide,TAT binding oligopeptide or TAT binding organic molecule is an amountcapable of causing the destruction of a cell, especially tumor, e.g.,cancer cell, either in vitro or in vivo. A “cytotoxic amount” of ananti-TAT antibody, TAT polypeptide, TAT binding oligopeptide or TATbinding organic molecule for purposes of inhibiting neoplastic cellgrowth may be determined empirically and in a routine manner.

[0564] The term “antibody” is used in the broadest sense andspecifically covers, for example, single anti-TAT monoclonal antibodies(including agonist, antagonist, and neutralizing antibodies), anti-TATantibody compositions with polyepitopic specificity, polyclonalantibodies, single chain anti-TAT antibodies, and fragments of anti-TATantibodies (see below) as long as they exhibit the desired biological orimmunological activity. The term “immunoglobulin” (Ig) is usedinterchangeable with antibody herein.

[0565] An “isolated antibody” is one which has been identified andseparated and/or recovered from a component of its natural environment.Contaminant components of its natural environment are materials whichwould interfere with diagnostic or therapeutic uses for the antibody,and may include enzymes, hormones, and other proteinaceous ornonproteinaceous solutes. In preferred embodiments, the antibody will bepurified (1) to greater than 95% by weight of antibody as determined bythe Lowry method, and most preferably more than 99% by weight, (2) to adegree sufficient to obtain at least 15 residues of N-terminal orinternal amino acid sequence by use of a spinning cup sequenator, or (3)to homogeneity by SDS-PAGE under reducing or nonreducing conditionsusing Coomassie blue or, preferably, silver stain. Isolated antibodyincludes the antibody in situ within recombinant cells since at leastone component of the antibody's natural environment will not be present.Ordinarily, however, isolated antibody will be prepared by at least onepurification step.

[0566] The basic 4-chain antibody unit is a heterotetramericglycoprotein composed of two identical light (L) chains and twoidentical heavy (H) chains (an IgM antibody consists of 5 of the basicheterotetramer unit along with an additional polypeptide called J chain,and therefore contain 10 antigen binding sites, while secreted IgAantibodies can polymerize to form polyvalent assemblages comprising 2-5of the basic 4-chain units along with J chain). In the case of IgGs, the4-chain unit is generally about 150,000 daltons. Each L chain is linkedto a H chain by one covalent disulfide bond, while the two H chains arelinked to each other by one or more disulfide bonds depending on the Hchain isotype. Each H and L chain also has regularly spaced intrachaindisulfide bridges. Each H chain has at the N-terminus, a variable domain(V_(H) followed by three constant domains (C_(H)) for each of the α andγ chains and four C_(H) domains for μ and ε isotypes. Each L chain hasat the N-terminus, a variable domain (V_(L)) followed by a constantdomain (C_(L)) at its other end. The V_(L) is aligned with the V_(H) andthe C_(L) is aligned with the first constant domain of the heavy chain(C_(H) 1). Particular amino acid residues are believed to form aninterface between the light chain and heavy chain variable domains. Thepairing of a V_(H) and V_(L) together forms a single antigen-bindingsite. For the structure and properties of the different classes ofantibodies, see, e.g., Basic and Clinical Immunology, 8th edition,Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton& Lange, Norwalk, Conn., 1994, page 71 and Chapter 6.

[0567] The L chain from any vertebrate species can be assigned to one oftwo clearly distinct types, called kappa and lambda, based on the aminoacid sequences of their constant domains. Depending on the amino acidsequence of the constant domain of their heavy chains (C_(H)),immunoglobulins can be assigned to different classes or isotypes. Thereare five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, havingheavy chains designated α, δ, ε, γ, and μ, respectively. The γ and αclasses are further divided into subclasses on the basis of relativelyminor differences in C_(H)sequence and function, e.g., humans expressthe following subclasses: IgG 1, IgG2, IgG3, IgG4, IgA1, and IgA2.

[0568] The term “variable” refers to the fact that certain segments ofthe variable domains differ extensively in sequence among antibodies.The V domain mediates antigen binding and define specificity of aparticular antibody for its particular antigen. However, the variabilityis not evenly distributed across the 110-amino acid span of the variabledomains. Instead, the V regions consist of relatively invariantstretches called framework regions (FRs) of 15-30 amino acids separatedby shorter regions of extreme variability called “hypervariable regions”that are each 9-12 amino acids long. The variable domains of nativeheavy and light chains each comprise four FRs, largely adopting aβ-sheet configuration, connected by three hypervariable regions, whichform loops connecting, and in some cases forming part of, the β-sheetstructure. The hypervariable regions in each chain are held together inclose proximity by the FRs and, with the hypervariable regions from theother chain, contribute to the formation of the antigen-binding site ofantibodies (see Kabat et al., Sequences of Proteins of ImmunologicalInterest, 5th Ed. Public Health Service, National Institutes of Health,Bethesda, Md. (1991)). The constant domains are not involved directly inbinding an antibody to an antigen, but exhibit various effectorfunctions, such as participation of the antibody in antibody dependentcellular cytotoxicity (ADCC).

[0569] The term “hypervariable region” when used herein refers to theamino acid residues of an antibody which are responsible forantigen-binding. The hypervariable region generally comprises amino acidresidues from a complementarity determining region” or “CDR” (e.g.around about residues 24-34 (L1), 50-56 (L2) and 89-97 (L3) in theV_(L), and around about 1-35 (H1), 50-65 (H2) and 95-102 (H3) in theV_(H); Kabat et al.Sequences of Proteins of Immunological Interest, 5thEd. Public Health Service, National Institutes of Health, Bethesda, Md.(1991)) and/or those residues from a “hypervariable loop” (e.g. residues26-32 (L1), 50-52 (L2) and 91-96 (L3) in the V_(L), and 26-32 (H1),53-55 (H2) and 96-101 (H3) in the V_(H); Chothia and Lesk J. Mol. Biol.196:901-917 (1987)).

[0570] The term “monoclonal antibody” as used herein refers to anantibody obtained from a population of substantially homogeneousantibodies, i.e., the individual antibodies comprising the populationare identical except for possible naturally occurring mutations that maybe present in minor amounts. Monoclonal antibodies are highly specific,being directed against a single antigenic site. Furthermore, in contrastto polyclonal antibody preparations which include different antibodiesdirected against different determinants (epitopes), each monoclonalantibody is directed against a single determinant on the antigen. Inaddition to their specificity, the monoclonal antibodies areadvantageous in that they may be synthesized uncontaminated by otherantibodies. The modifier “monoclonal” is not to be construed asrequiring production of the antibody by any particular method. Forexample, the monoclonal antibodies useful in the present invention maybe prepared by the hybridoma methodology first described by Kohler etal., Nature, 256:495 (1975), or may be made using recombinant DNAmethods in bacterial, eukaryotic animal or plant cells (see, e.g., U.S.Pat. No. 4,816,567). The “monoclonal antibodies” may also be isolatedfrom phage antibody libraries using the techniques described in Clacksonet al., Nature, 352:624-628 (1991) and Marks et al., J. Mol. Biol.,222:581-597 (1991), for example.

[0571] The monoclonal antibodies herein include “chimeric” antibodies inwhich a portion of the heavy and/or light chain is identical with orhomologous to corresponding sequences in antibodies derived from aparticular species or belonging to a particular antibody class orsubclass, while the remainder of the chain(s) is identical with orhomologous to corresponding sequences in antibodies derived from anotherspecies or belonging to another antibody class or subclass, as well asfragments of such antibodies, so long as they exhibit the desiredbiological activity (see U.S. Pat. No. 4,816,567; and Morrison et al.,Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)). Chimeric antibodies ofinterest herein include “primatized” antibodies comprising variabledomain antigen-binding sequences derived from a non-human primate (e.g.Old World Monkey, Ape etc), and human constant region sequences.

[0572] An “intact” antibody is one which comprises an antigen-bindingsite as well as a C_(L) and at least heavy chain constant domains,C_(H)1, C_(H)2 and C_(H)3. The constant domains may be native sequenceconstant domainse(g. human native sequence constant domains) or aminoacid sequence variant thereof. Preferably, the intact antibody has oneor more effector functions.

[0573] “Antibody fragments” comprise a portion of an intact antibody,preferably the antigen binding or variable region of the intactantibody. Examples of antibody fragments include Fab, Fab′, F(ab′)₂, andFv fragments; diabodies; linear antibodies (see U.S. Pat. No. 5,641,870,Example 2; Zapata et al., Protein Eng. 8(10): 1057-1062 [1995]);single-chain antibody molecules; and multispecific antibodies formedfrom antibody fragments.

[0574] Papain digestion of antibodies produces two identicalantigen-binding fragments, called “Fab” fragments, and a residual “Fc”fragment, a designation reflecting the ability to crystallize readily.The Fab fragment consists of an entire L chain along with the variableregion domain of the H chain (V_(H)), and the first constant domain ofone heavy chain (C_(H)1). Each Fab fragment is monovalent with respectto antigen binding, i.e., it has a single antigen-binding site. Pepsintreatment of an antibody yields a single large F(ab′)₂ fragment whichroughly corresponds to two disulfide linked Fab fragments havingdivalent antigen-binding activity and is still capable of cross-linkingantigen. Fab′ fragments differ from Fab fragments by having additionalfew residues at the carboxy terminus of the C_(H)1 domain including oneor more cysteines from the antibody hinge region. Fab′-SH is thedesignation herein for Fab′ in which the cysteine residue(s) of theconstant domains bear a free thiol group. F(ab′)₂ antibody fragmentsoriginally were produced as pairs of Fab′ fragments which have hingecysteines between them. Other chemical couplings of antibody fragmentsare also known.

[0575] The Fc fragment comprises the carboxy-terminal portions of both Hchains held together by disulfides. The effector functions of antibodiesare determined by sequences in the Fc region, which region is also thepart recognized by Fc receptors (FcR) found on certain types of cells.

[0576] “Fv” is the minimum antibody fragment which contains a completeantigen-recognition and -binding site. This fragment consists of a dimerof one heavy- and one light-chain variable region domain in tight,non-covalent association. From the folding of these two domains emanatesix hypervariable loops (3 loops each from the H and L chain) thatcontribute the amino acid residues for antigen binding and conferantigen binding specificity to the antibody. However, even a singlevariable domain (or half of an Fv comprising only three CDRs specificfor an antigen) has the ability to recognize and bind antigen, althoughat a lower affinity than the entire binding site.

[0577] “Single-chain Fv” also abbreviated as “sFv” or “scFv” areantibody fragments that comprise the V_(H) and V_(L) antibody domainsconnected into a single polypeptide chain. Preferably, the sFvpolypeptide further comprises a polypeptide linker between the V_(H) andV_(L) domains which enables the sFv to form the desired structure forantigen binding. For a review of sFv, see Pluckthun in The Pharmacologyof Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds.,Springer-Verlag, New York, pp. 269-315 (1994); Borrebaeck 1995, infra.

[0578] The term “diabodies” refers to small antibody fragments preparedby constructing sFv fragments (see preceding paragraph) with shortlinkers (about 5-10 residues) between the V_(H) and V_(L) domains suchthat inter-chain but not intra-chain pairing of the V domains isachieved, resulting in a bivalent fragment, i.e., fragment having twoantigen-binding sites. Bispecific diabodies are heterodimers of two“crossover” sFv fragments in which the V_(H) and V_(L) domains of thetwo antibodies are present on different polypeptide chains. Diabodiesare described more fully in, for example, EP 404,097; WO 93/11161; andHollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993).

[0579] “Humanized” forms of non-human (e.g., rodent) antibodies arechimeric antibodies that contain minimal sequence derived from thenon-human antibody. For the most part, humanized antibodies are humanimmunoglobulins (recipient antibody) in which residues from ahypervariable region of the recipient are replaced by residues from ahypervariable region of a non-human species (donor antibody) such asmouse, rat. rabbit or non-human primate having the desired antibodyspecificity, affinity, and capability. In some instances, frameworkregion (FR) residues of the human immunoglobulin are replaced bycorresponding non-human residues. Furthermore, humanized antibodies maycomprise residues that are not found in the recipient antibody or in thedonor antibody. These modifications are made to further refine antibodyperformance. In general, the humanized antibody will comprisesubstantially all of at least one, and typically two, variable domains,in which all or substantially all of the hypervariable loops correspondto those of a non-human immunoglobulin and all or substantially all ofthe FRs are those of a human immunoglobulin sequence. The humanizedantibody optionally also will comprise at least a portion of animmunoglobulin constant region (Fc), typically that of a humanimmunoglobulin. For further details, see Jones et al., Nature321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); andPresta, Curr. Op. Struct. Biol. 2:593-596 (1992).

[0580] A “species-dependent antibody,” e.g., a mammalian anti-human IgEantibody, is an antibody which has a stronger binding affinity for anantigen from a first mammalian species than it has for a homologue ofthat antigen from a second mammalian species. Normally, thespecies-dependent antibody “bind specifically” to a human antigen (i.e.,has a binding affinity (Kd) value of no more than about 1×10⁻⁷ M,preferably no more than about 1×10⁻⁸ and most preferably no more thanabout 1×10⁻⁹ M) but has a binding affinity for a homologue of theantigen from a second non-human mammalian species which is at leastabout 50 fold, or at least about 500 fold, or at least about 1000 fold,weaker than its binding affinity for the human antigen. Thespecies-dependent antibody can be of any of the various types ofantibodies as defined above, but preferably is a humanized or humanantibody.

[0581] A “TAT binding oligopeptide” is an oligopeptide that binds,preferably specifically, to a TAT polypeptide as described herein. TATbinding oligopeptides may be chemically synthesized using knownoligopeptide synthesis methodology or may be prepared and purified usingrecombinant technology. TAT binding oligopeptides are usually at leastabout 5 amino acids in length, alternatively at least about 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81,82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99,or 100 amino acids in length or more, wherein such oligopeptides thatare capable of binding, preferably specifically, to a TAT polypeptide asdescribed herein. TAT binding oligopeptides may be identified withoutundue experimentation using well known techniques. In this regard, it isnoted that techniques for screening oligopeptide libraries foroligopeptides that are capable of specifically binding to a polypeptidetarget are well known in the art (see, e.g., U.S. Pat. Nos. 5,556,762,5,750,373, 4,708,871, 4,833,092, 5,223,409, 5,403,484, 5,571,689,5,663,143; PCT Publication Nos. WO 84/03506 and WO84/03564; Geysen etal., Proc. Natl. Acad. Sci. U.S.A., 81:3998-4002 (1984); Geysen et al.,Proc. Natl. Acad. Sci. U.S.A., 82:178-182 (1985); Geysen et al., inSynthetic Peptides as Antigens, 130-149 (1986); Geysen et al., J.Immunol. Meth., 102:259-274 (1987); Schoofs et al., J. Immunol.,140:611-616 (1988), Cwirla, S. E. et al. (1990) Proc. Natl. Acad. Sci.USA, 87:6378; Lowman, H. B. et al. (1991) Biochemistry, 30:10832;Clackson, T. et al. (1991) Nature, 352: 624; Marks, J. D. et al. (1991),J. Mol. Biol., 222:581; Kang, A. S. et al. (1991) Proc. Natl. Acad. Sci.USA, 88:8363, and Smith, G. P. (1991) Current Opin. Biotechnol., 2:668).

[0582] A “TAT binding organic molecule” is an organic molecule otherthan an oligopeptide or antibody as defined herein that binds,preferably specifically, to a TAT polypeptide as described herein. TATbinding organic molecules may be identified and chemically synthesizedusing known methodology (see, e.g., PCT Publication Nos. WO00/00823 andWO00/39585). TAT binding organic molecules are usually less than about2000 daltons in size, alternatively less than about 1500, 750, 500, 250or 200 daltons in size, wherein such organic molecules that are capableof binding, preferably specifically, to a TAT polypeptide as describedherein may be identified without undue experimentation using well knowntechniques. In this regard, it is noted that techniques for screeningorganic molecule libraries for molecules that are capable of binding toa polypeptide target are well known in the art (see, e.g., PCTPublication Nos. WO00/00823 and WO00/39585).

[0583] An antibody, oligopeptide or other organic molecule “which binds”an antigen of interest, e.g. a tumor-associated polypeptide antigentarget, is one that binds the antigen with sufficient affinity such thatthe antibody, oligopeptide or other organic molecule is useful as adiagnostic and/or therapeutic agent in targeting a cell or tissueexpressing the antigen, and does not significantly cross-react withother proteins. In such embodiments, the extent of binding of theantibody, oligopeptide or other organic molecule to a “non-target”protein will be less than about 10% of the binding of the antibody,oligopeptide or other organic molecule to its particular target proteinas determined by fluorescence activated cell sorting (FACS) analysis orradioimmunoprecipitation (RIA). With regard to the binding of anantibody, oligopeptide or other organic molecule to a target molecule,the term “specific binding” or “specifically binds to” or is “specificfor” a particular polypeptide or an epitope on a particular polypeptidetarget means binding that is measurably different from a non-specificinteraction. Specific binding can be measured, for example, bydetermining binding of a molecule compared to binding of a controlmolecule, which generally is a molecule of similar structure that doesnot have binding activity. For example, specific binding can bedetermined by competition with a control molecule that is similar to thetarget, for example, an excess of non-labeled target. In this case,specific binding is indicated if the binding of the labeled target to aprobe is competitively inhibited by excess unlabeled target. The term“specific binding” or “specifically binds to” or is “specific for” aparticular polypeptide or an epitope on a particular polypeptide targetas used herein can be exhibited, for example, by a molecule having a Kdfor the target of at least about 10⁻⁴ M, alternatively at least about10⁻⁵ M, alternatively at least about 10⁻⁶ M, alternatively at leastabout 10⁻⁷ M, alternatively at least about 10⁻⁸ M, alternatively atleast about 10⁻⁹ M, alternatively at least about 10⁻¹⁰ M, alternativelyat least about 10⁻¹¹ M, alternatively at least about 10⁻¹² M, orgreater. In one embodiment, the term “specific binding” refers tobinding where a molecule binds to a particular polypeptide or epitope ona particular polypeptide without substantially binding to any otherpolypeptide or polypeptide epitope.

[0584] An antibody, oligopeptide or other organic molecule that“inhibits the growth of tumor cells expressing a TAT polypeptide” or a“growth inhibitory” antibody, oligopeptide or other organic molecule isone which results in measurable growth inhibition of cancer cellsexpressing or overexpressing the appropriate TAT polypeptide. The TATpolypeptide may be a transmembrane polypeptide expressed on the surfaceof a cancer cell or may be a polypeptide that is produced and secretedby a cancer cell. Preferred growth inhibitory anti-TAT antibodies,oligopeptides or organic molecules inhibit growth of TAT-expressingtumor cells by greater than 20%, preferably from about 20% to about 50%,and even more preferably, by greater than 50% (e.g., from about 50% toabout 100%) as compared to the appropriate control, the controltypically being tumor cells not treated with the antibody, oligopeptideor other organic molecule being tested. In one embodiment, growthinhibition can be measured at an antibody concentration of about 0.1 to30 μg/ml or about 0.5 nM to 200 nM in cell culture, where the growthinhibition is determined 1-10 days after exposure of the tumor cells tothe antibody. Growth inhibition of tumor cells in vivo can be determinedin various ways such as is described in the Experimental Examplessection below. The antibody is growth inhibitory in vivo ifadministration of the anti-TAT antibody at about 1 μg/kg to about 100mg/kg body weight results in reduction in tumor size or tumor cellproliferation within about 5 days to 3 months from the firstadministration of the antibody, preferably within about 5 to 30 days.

[0585] An antibody, oligopeptide or other organic molecule which“induces apoptosis” is one which induces programmed cell death asdetermined by binding of annexin V, fragmentation of DNA, cellshrinkage, dilation of endoplasmic reticulum, cell fragmentation, and/orformation of membrane vesicles (called apoptotic bodies). The cell isusually one which overexpresses a TAT polypeptide. Preferably the cellis a tumor cell, e.g., a prostate, breast, ovarian, stomach,endometrial, lung, kidney, colon, bladder cell. Various methods areavailable for evaluating the cellular events associated with apoptosis.For example, phosphatidyl serine (PS) translocation can be measured byannexin binding; DNA fragmentation can be evaluated through DNAladdering; and nuclear/chromatin condensation along with DNAfragmentation can be evaluated by any increase in hypodiploid cells.Preferably, the antibody, oligopeptide or other organic molecule whichinduces apoptosis is one which results in about 2 to 50 fold, preferablyabout 5 to 50 fold, and most preferably about 10 to 50 fold, inductionof annexin binding relative to untreated cell in an annexin bindingassay.

[0586] Antibody “effector functions” refer to those biologicalactivities attributable to the Fc region (a native sequence Fc region oramino acid sequence variant Fc region) of an antibody, and vary with theantibody isotype. Examples of antibody effector functions include: C1qbinding and complement dependent cytotoxicity; Fc receptor binding;antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g., B cell receptor); and B cellactivation.

[0587] “Antibody-dependent cell-mediated cytotoxicity” or “ADCC” refersto a form of cytotoxicity in which secreted Ig bound onto Fc receptors(FcRs) present on certain cytotoxic cells (e.g., Natural Killer (NK)cells, neutrophils, and macrophages) enable these cytotoxic effectorcells to bind specifically to an antigen-bearing target cell andsubsequently kill the target cell with cytotoxins. The antibodies “arm”the cytotoxic cells and are absolutely required for such killing. Theprimary cells for mediating ADCC, NK cells, express Fc γRIII only,whereas monocytes express FcγRI, FcγRII and FcγRIII. FcR expression onhematopoietic cells is summarized in Table 3 on page 464 of Ravetch andKinet, Annu. Rev. Immunol. 9:457-92 (1991). To assess ADCC activity of amolecule of interest, an in vitro ADCC assay, such as that described inU.S. Pat. No. 5,500,362 or 5,821,337 may be performed. Useful effectorcells for such assays include peripheral blood mononuclear cells (PBMC)and Natural Killer (NK) cells. Alternatively, or additionally, ADCCactivity of the molecule of interest may be assessed in vivo, e.g., in aanimal model such as that disclosed in Clynes et al. (USA) 95:652-656(1998).

[0588] “Fc receptor” or “FcR” describes a receptor that binds to the Fcregion of an antibody. The preferred FcR is a native sequence human FcR.Moreover, a preferred FcR is one which binds an IgG antibody (a gammareceptor) and includes receptors of the FcγRI, FcγRII and FcγRIIIsubclasses, including allelic variants and alternatively spliced formsof these receptors. FcγRII receptors include FcγRIIA (an “activatingreceptor”) and FcγRIIB (an “inhibiting receptor”), which have similaramino acid sequences that differ primarily in the cytoplasmic domainsthereof. Activating receptor FcγRIIA contains an immunoreceptortyrosine-based activation motif(ITAM) in its cytoplasmic domain.Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-basedinhibition motif (ITIM) in its cytoplasmic domain. (see review M. inDaëron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed inRavetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991); Capel et al.,Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med.126:33041 (1995). Other FcRs, including those to be identified in thefuture, are encompassed by the term “FcR” herein. The term also includesthe neonatal receptor, FcRn, which is responsible for the transfer ofmaternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976) andKim et al., J. Immunol. 24:249 (1994)).

[0589] “Human effector cells” are leukocytes which express one or moreFcRs and perform effector functions. Preferably, the cells express atleast FcγRIII and perform ADCC effector function. Examples of humanleukocytes which mediate ADCC include peripheral blood mononuclear cells(PBMC), natural killer (NK) cells, monocytes, cytotoxic T cells andneutrophils; with PBMCs and NK cells being preferred. The effector cellsmay be isolated from a native source, e.g., from blood.

[0590] “Complement dependent cytotoxicity” or “CDC” refers to the lysisof a target cell in the presence of complement. Activation of theclassical complement pathway is initiated by the binding of the firstcomponent of the complement system (C1q) to antibodies (of theappropriate subclass) which are bound to their cognate antigen. Toassess complement activation, a CDC assay, e.g., as described inGazzano-Santoro et al. J. Immunol. Methods 202:163 (1996), may beperformed.

[0591] The terms “cancer” and “cancerous” refer to or describe thephysiological condition in mammals that is typically characterized byunregulated cell growth. Examples of cancer include, but are not limitedto, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoidmalignancies. More particular examples of such cancers include squamouscell cancer (e.g., epithelial squamous cell cancer), lung cancerincluding small-cell lung cancer, non-small cell lung cancer,adenocarcinoma of the lung and squamous carcinoma of the lung, cancer ofthe peritoneum, hepatocellular cancer, gastric or stomach cancerincluding gastrointestinal cancer, pancreatic cancer, glioblastoma,cervical cancer, ovarian cancer, liver cancer, bladder cancer, cancer ofthe urinary tract, hepatoma, breast cancer, colon cancer, rectal cancer,colorectal cancer, endometrial or uterine carcinoma, salivary glandcarcinoma, kidney or renal cancer, prostate cancer, vulval cancer,thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma,melanoma, multiple myeloma and B-cell lymphoma, brain, as well as headand neck cancer, and associated metastases.

[0592] The terms “cell proliferative disorder” and “proliferativedisorder” refer to disorders that are associated with some degree ofabnormal cell proliferation. In one embodiment, the cell proliferativedisorder is cancer.

[0593] “Tumor”, as used herein, refers to all neoplastic cell growth andproliferation, whether malignant or benign, and all pre-cancerous andcancerous cells and tissues.

[0594] An antibody, oligopeptide or other organic molecule which“induces cell death” is one which causes a viable cell to becomenonviable. The cell is one which expresses a TAT polypeptide, preferablya cell that overexpresses a TAT polypeptide as compared to a normal cellof the same tissue type. The TAT polypeptide may be a transmembranepolypeptide expressed on the surface of a cancer cell or may be apolypeptide that is produced and secreted by a cancer cell. Preferably,the cell is a cancer cell, e.g., a breast, ovarian, stomach,endometrial, salivary gland, lung, kidney, colon, thyroid, pancreatic orbladder cell. Cell death in vitro may be determined in the absence ofcomplement and immune effector cells to distinguish cell death inducedby antibody-dependent cell-mediated cytotoxicity (ADCC) or complementdependent cytotoxicity (CDC). Thus, the assay for cell death may beperformed using heat inactivated serum (i.e., in the absence ofcomplement) and in the absence of immune effector cells. To determinewhether the antibody, oligopeptide or other organic molecule is able toinduce cell death, loss of membrane integrity as evaluated by uptake ofpropidium iodide (PI), trypan blue (see Moore et al. Cytotechnology17:1-11 (1995)) or 7AAD can be assessed relative to untreated cells.Preferred cell death-inducing antibodies, oligopeptides or other organicmolecules are those which induce PI uptake in the PI uptake assay inBT474 cells.

[0595] A “TAT-expressing cell” is a cell which expresses an endogenousor transfected TAT polypeptide either on the cell surface or in asecreted form. A “TAT-expressing cancer” is a cancer comprising cellsthat have a TAT polypeptide present on the cell surface or that produceand secrete a TAT polypeptide. A “TAT-expressing cancer” optionallyproduces sufficient levels of TAT polypeptide on the surface of cellsthereof, such that an anti-TAT antibody, oligopeptide of other organicmolecule can bind thereto and have a therapeutic effect with respect tothe cancer. In another embodiment, a “TAT-expressing cancer” optionallyproduces and secretes sufficient levels of TAT polypeptide, such that ananti-TAT antibody, oligopeptide ot other organic molecule antagonist canbind thereto and have a therapeutic effect with respect to the cancer.With regard to the latter, the antagonist may be an antisenseoligonucleotide which reduces, inhibits or prevents production andsecretion of the secreted TAT polypeptide by tumor cells. A cancer which“overexpresses” a TAT polypeptide is one which has significantly higherlevels of TAT polypeptide at the cell surface thereof, or produces andsecretes, compared to a noncancerous cell of the same tissue type. Suchoverexpression may be caused by gene amplification or by increasedtranscription or translation. TAT polypeptide overexpression may bedetermined in a diagnostic or prognostic assay by evaluating increasedlevels of the TAT protein present on the surface of a cell, or secretedby the cell (e.g., via an immunohistochemistry assay using anti-TATantibodies prepared against an isolated TAT polypeptide which may beprepared using recombinant DNA technology from an isolated nucleic acidencoding the TAT polypeptide; FACS analysis, etc.). Alternatively, oradditionally, one may measure levels of TAT polypeptide-encoding nucleicacid or mRNA in the cell, e.g., via fluorescent in situ hybridizationusing a nucleic acid based probe corresponding to a TAT-encoding nucleicacid or the complement thereof; (FISH; see WO98/45479 published October,1998), Southern blotting, Northern blotting, or polymerase chainreaction (PCR) techniques, such as real time quantitative PCR (RT-PCR).One may also study TAT polypeptide overexpression by measuring shedantigen in a biological fluid such as serum, e.g, using antibody-basedassays (see also, e.g., U.S. Pat. No. 4,933,294 issued Jun. 12, 1990;WO91/05264 published Apr. 18, 199 1; U.S. Pat. No. 5,401,638 issued Mar.28, 1995; and Sias et al., J. Immunol. Methods 132:73-80 (1990)). Asidefrom the above assays, variouin vivo assays are available to the skilledpractitioner. For example, one may expose cells within the body of thepatient to an antibody which is optionally labeled with a detectablelabel, e.g., a radioactive isotope, and binding of the antibody to cellsin the patient can be evaluated, e.g., by external scanning forradioactivity or by analyzing a biopsy taken from a patient previouslyexposed to the antibody.

[0596] As used herein, the term “immunoadhesin” designates antibody-likemolecules which combine the binding specificity of a heterologousprotein (an “adhesin”) with the effector functions of immunoglobulinconstant domains. Structurally, the immunoadhesins comprise a fusion ofan amino acid sequence with the desired binding specificity which isother than the antigen recognition and binding site of an antibody(i.e., is “heterologous”), and an immunoglobulin constant domainsequence. The adhesin part of an immunoadhesin molecule typically is acontiguous amino acid sequence comprising at least the binding site of areceptor or a ligand. The immunoglobulin constant domain sequence in theimmunoadhesin may be obtained from any immunoglobulin, such as IgG-1,IgG-2, IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE,IgD or IgM.

[0597] The word “label” when used herein refers to a detectable compoundor composition which is conjugated directly or indirectly to theantibody, oligopeptide or other organic molecule so as to generate a“labeled” antibody, oligopeptide or other organic molecule. The labelmay be detectable by itself (e.g. radioisotope labels or fluorescentlabels) or, in the case of an enzymatic label, may catalyze chemicalalteration of a substrate compound or composition which is detectable.

[0598] The term “cytotoxic agent” as used herein refers to a substancethat inhibits or prevents the function of cells and/or causesdestruction of cells. The term is intended to include radioactiveisotopes (e.g., At²¹¹, I¹³¹, I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³²and radioactive isotopes of Lu), chemotherapeutic agents e.g.methotrexate, adriamicin, vinca alkaloids (vincristine, vinblastine,etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil,daunorubicin or other intercalating agents, enzymes and fragmentsthereof such as nucleolytic enzymes, antibiotics, and toxins such assmall molecule toxins or enzymatically active toxins of bacterial,fungal, plant or animal origin, including fragments and/or variantsthereof, and the various antitumor or anticancer agents disclosed below.Other cytotoxic agents are described below. A tumoricidal agent causesdestruction of tumor cells.

[0599] A “growth inhibitory agent” when used herein refers to a compoundor composition which inhibits growth of a cell, especially aTAT-expressing cancer cell, either in vitro or in vivo. Thus, the growthinhibitory agent may be one which significantly reduces the percentageof TAT-expressing cells in S phase. Examples of growth inhibitory agentsinclude agents that block cell cycle progression (at a place other thanS phase), such as agents that induce G1 arrest and M-phase arrest.Classical M-phase blockers include the vincas (vincristine andvinblastine), taxanes, and topoisomerase II inhibitors such asdoxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. Thoseagents that arrest G1 also spill over into S-phase arrest, for example,DNA alkylating agents such as tamoxifen, prednisone, dacarbazine,mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C.Further information can be found in The Molecular Basis of Cancer,Mendelsohn and Israel, eds., Chapter 1, entitled “Cell cycle regulation,oncogenes, and antineoplastic drugs” by Murakami et al. (WB Saunders:Philadelphia, 1995), especially p. 13. The taxanes (paclitaxel anddocetaxel) are anticancer drugs both derived from the yew tree.Docetaxel (TAXOTERE®, Rhone-Poulenc Rorer), derived from the Europeanyew, is a semisynthetic analogue of paclitaxel (TAXOL®, Bristol-MyersSquibb). Paclitaxel and docetaxel promote the assembly of microtubulesfrom tubulin dimers and stabilize microtubules by preventingdepolymerization, which results in the inhibition of mitosis in cells.

[0600] “Doxorubicin” is an anthracycline antibiotic. The full chemicalname of doxorubicin is(8S-cis)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexapyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-naphthacenedione.

[0601] The term “cytokine” is a generic term for proteins released byone cell population which act on another cell as intercellularmediators. Examples of such cytokines are lymphokines, monokines, andtraditional polypeptide hormones. Included among the cytokines aregrowth hormone such as human growth hormone, N-methionyl human growthhormone, and bovine growth hormone; parathyroid hormone; thyroxine;insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones such asfollicle stimulating hormone (FSH), thyroid stimulating hormone (TSH),and luteinizing hormone (LH); hepatic growth factor; fibroblast growthfactor; prolactin; placental lactogen; tumor necrosis factor-α and -β;mullerian-inhibiting substance; mouse gonadotropin-associated peptide;inhibin; activin; vascular endothelial growth factor; integrin;thrombopoietin (TPO); nerve growth factors such as NGF-β;platelet-growth factor; transforming growth factors (TGFs) such as TGF-αand TGF-β; insulin-like growth factor-I and -II; erythropoietin (EPO);osteoinductive factors; interferons such as interferon -α, -β, and -γ;colony stimulating factors (CSFs) such as macrophage-CSF (M-CSF);granulocyte-macrophage-CSF (GM-CSF); and granulocyte-CSF (G-CSF);interleukins (ILs) such as IL-1, IL-1a, IL-2, IL-3, IL-4, IL-5, IL-6,IL-7, IL-8, IL-9, IL-11, IL-12; a tumor necrosis factor such as TNF-α orTNF-β; and other polypeptide factors including LIF and kit ligand (KL).As used herein, the term cytokine includes proteins from natural sourcesor from recombinant cell culture and biologically active equivalents ofthe native sequence cytokines.

[0602] The term “package insert” is used to refer to instructionscustomarily included in commercial packages of therapeutic products,that contain information about the indications, usage, dosage,administration, contraindications and/or warnings concerning the use ofsuch therapeutic products. TABLE 2 TAT XXXXXXXXXXXXXXX (Length = 15amino acids) Comparison XXXXXYYYYYYY (Length = 12 amino acids) Protein

[0603] TABLE 3 TAT XXXXXXXXXX (Length = 10 amino acids) ComparisonXXXXXYYYYYYZZYZ (Length = 15 amino acids) Protein

[0604] TABLE 4 TAT-DNA NNNNNNNNNNNNNN (Length = 14 nucleotides)Comparison NNNNNNLLLLLLLLLL (Length = 16 nucleotides) DNA

[0605] TABLE 5 TAT-DNA NNNNNNNNNNNN (Length = 12 nucleotides) ComparisonNNNNLLLVV (Length = 9 nucleotides) DNA

[0606] II. Compositions and Methods of the Invention

[0607] A. Anti-TAT Antibodies

[0608] In one embodiment, the present invention provides anti-TATantibodies which may find use herein as therapeutic and/ordiagnosticagents. Exemplary antibodies include polyclonal, monoclonal, humanized,bispecific, and heteroconjugate antibodies.

[0609] 1. Polyclonal Antibodies

[0610] Polyclonal antibodies are preferably raised in animals bymultiple subcutaneous (sc) or intraperitoneal (ip) injections of therelevant antigen and an adjuvant. It may be useful to conjugate therelevant antigen (especially when synthetic peptides are used) to aprotein that is immunogenic in the species to be immunized. For example,the antigen can be conjugated to keyhole limpet hemocyanin (KLH), serumalbumin, bovine thyroglobulin, or soybean trypsin inhibitor, using abifunctional or derivatizing agent, e.g., maleimidobenzoylsulfosuccinimide ester (conjugation through cysteine residues),N-hydroxysuccinimide (through lysine residues), glutaraldehyde, succinicanhydride, SOCl₂, or R¹N═C═NR, where R and R¹ are different alkylgroups.

[0611] Animals are immunized against the antigen, immunogenicconjugates, or derivatives by combining, e.g., 100 μg or 5 μg of theprotein or conjugate (for rabbits or mice, respectively) with 3 volumesof Freund's complete adjuvant and injecting the solution intradermallyat multiple sites. One month later, the animals are boosted with ⅕ to{fraction (1/10)} the original amount of peptide or conjugate inFreund's complete adjuvant by subcutaneous injection at multiple sites.Seven to 14 days later, the animals are bled and the serum is assayedfor antibody titer. Animals are boosted until the titer plateaus.Conjugates also can be made in recombinant cell culture as proteinfusions. Also, aggregating agents such as alum are suitably used toenhance the immune response.

[0612] 2. Monoclonal Antibodies

[0613] Monoclonal antibodies may be made using the hybridoma methodfirst described by Kohler et al., Nature, 256:495 (1975), or may be madeby recombinant DNA methods (U.S. Pat. No. 4,816,567).

[0614] In the hybridoma method, a mouse or other appropriate hostanimal, such as a hamster, is immunized as described above to elicitlymphocytes that produce or are capable of producing antibodies thatwill specifically bind to the protein used for immunization.Alternatively, lymphocytes may be immunized in vitro. Afterimmunization, lymphocytes are isolated and then fused with a myelomacell line using a suitable fusing agent, such as polyethylene glycol, toform a hybridoma cell (Goding, Monoclonal Antibodies: Principles andPractice, pp.59-103 (Academic Press, 1986)).

[0615] The hybridoma cells thus prepared are seeded and grown in asuitable culture medium which medium preferably contains one or moresubstances that inhibit the growth or survival of the unfused, parentalmyeloma cells (also referred to as fusion partner). For example, if theparental myeloma cells lack the enzyme hypoxanthine guaninephosphoribosyl transferase (HGPRT or HPRT), the selective culture mediumfor the hybridomas typically will include hypoxanthine, aminopterin, andthymidine (HAT medium), which substances prevent the growth ofHGPRT-deficient cells.

[0616] Preferred fusion partner myeloma cells are those that fuseefficiently, support stable high-level production of antibody by theselected antibody-producing cells, and are sensitive to a selectivemedium that selects against the unfused parental cells. Preferredmyeloma cell lines are murine myeloma lines, such as those derived fromMOPC-21 and MPC-11 mouse tumors available from the Salk Institute CellDistribution Center, San Diego, Calif. USA, and SP-2 and derivativese.g., X63-Ag8-653 cells available from the American Type CultureCollection, Manassas, Va., USA. Human myeloma and mouse-humanheteromyeloma cell lines also have been described for the production ofhuman monoclonal antibodies (Kozbor, J. Immunol., 133:3001 (1984); andBrodeur et al., Monoclonal Antibody Production Techniques andApplications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987)).

[0617] Culture medium in which hybridoma cells are growing is assayedfor production of monoclonal antibodies directed against the antigen.Preferably, the binding specificity of monoclonal antibodies produced byhybridoma cells is determined by immunoprecipitation or by an in vitrobinding assay, such as radioimmunoassay (RIA) or enzyme-linkedimmunosorbent assay (ELISA).

[0618] The binding affinity of the monoclonal antibody can, for example,be determined by the Scatchard analysis described in Munson et al.,Anal. Biochem., 107:220 (1980).

[0619] Once hybridoma cells that produce antibodies of the desiredspecificity, affinity, and/or activity are identified, the clones may besubcloned by limiting dilution procedures and grown by standard methods(Goding, Monoclonal Antibodies: Principles and Practice, pp.59-103(Academic Press, 1986)). Suitable culture media for this purposeinclude, for example, D-MEM or RPMI-1640 medium. In addition, thehybridoma cells may be grown in vivo as ascites tumors in an animale.g,, by i.p. injection of the cells into mice.

[0620] The monoclonal antibodies secreted by the subclones are suitablyseparated from the culture medium, ascites fluid, or serum byconventional antibody purification procedures such as, for example,affinity chromatography (e.g., using protein A or protein G-Sepharose)or ion-exchange chromatography, hydroxylapatite chromatography, gelelectrophoresis, dialysis, etc.

[0621] DNA encoding the monoclonal antibodies is readily isolated andsequenced using conventional procedures (e.g., by using oligonucleotideprobes that are capable of binding specifically to genes encoding theheavy and light chains of murine antibodies). The hybridoma cells serveas a preferred source of such DNA. Once isolated, the DNA may be placedinto expression vectors, which are then transfected into host cells suchas E. coli cells, simian COS cells, Chinese Hamster Ovary (CHO) cells,or myeloma cells that do not otherwise produce antibody protein, toobtain the synthesis of monoclonal antibodies in the recombinant hostcells. Review articles on recombinant expression in bacteria of DNAencoding the antibody include Skerra et al., Curr. Opinion in Immunol.,5:256-262 (1993) and Pluckthun, Immunol. Revs. 130:151-188 (1992).

[0622] In a further embodiment, monoclonal antibodies or antibodyfragments can be isolated from antibody phage libraries generated usingthe techniques described in McCafferty et al., Nature, 348:552-554(1990). Clackson et al., Nature, 352:624-628 (1991) and Marks et al., J.Mol. Biol., 222:581-597 (1991) describe the isolation of murine andhuman antibodies, respectively, using phage libraries. Subsequentpublications describe the production of high affinity (nM range) humanantibodies by chain shuffling (Marks et al., Bio/Technology, 10:779-783(1992)), as well as combinatorial infection and in vivo recombination asa strategy for constructing very large phage libraries (Waterhouse etal., Nuc. Acids. Res. 21:2265-2266 (1993)). Thus, these techniques areviable alternatives to traditional monoclonal antibody hybridomatechniques for isolation of monoclonal antibodies.

[0623] The DNA that encodes the antibody may be modified to producechimeric or fusion antibody polypeptides, for example, by substitutinghuman heavy chain and light chain constant domain (C_(H) and C_(L))sequences for the homologous murine sequences (U.S. Pat. No.4,816,567;and Morrison, et al., Proc. Natl Acad. Sci. USA, 81:6851 (1984)), or byfusing the immunoglobulin coding sequence with all or part of the codingsequence for a non-immunoglobulin polypeptide (heterologouspolypeptide). The non-immunoglobulin polypeptide sequences cansubstitute for the constant domains of an antibody, or they aresubstituted for the variable domains of one antigen-combining site of anantibody to create a chimeric bivalent antibody comprising oneantigen-combining site having specificity for an antigen and anotherantigen-combining site having specificity for a different antigen.

[0624] 3. Human and Humanized Antibodies

[0625] The anti-TAT antibodies of the invention may further comprisehumanized antibodies or human antibodies. Humanized forms of non-human(e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulinchains or fragments thereof (such as Fv, Fab, Fab′, F(ab′)₂ or otherantigen-binding subsequences of antibodies) which contain minimalsequence derived from non-human immunoglobulin. Humanized antibodiesinclude human immunoglobulins (recipient antibody) in which residuesfrom a complementary determining region (CDR) of the recipient arereplaced by residues from a CDR of a non-human species (donor antibody)such as mouse, rat or rabbit having the desired specificity, affinityand capacity. In some instances, Fv framework residues of the humanimmunoglobulin are replaced by corresponding non-human residues.Humanized antibodies may also comprise residues which are found neitherin the recipient antibody nor in the imported CDR or frameworksequences. In general, the humanized antibody will comprisesubstantially all of at least one, and typically two, variable domains,in which all or substantially all of the CDR regions correspond to thoseof a non-human immunoglobulin and all or substantially all of the FRregions are those of a human immunoglobulin consensus sequence. Thehumanized antibody optimally also will comprise at least a portion of animmunoglobulin constant region (Fc), typically that of a humanimmunoglobulin [Jones et al., Nature 321:522-525 (1986); Riechmann etal., Nature, 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol.,2:593-596 (1992)].

[0626] Methods for humanizing non-human antibodies are well known in theart. Generally, a humanized antibody has one or more amino acid residuesintroduced into it from a source which is non-human. These non-humanamino acid residues are often referred to as “import” residues, whichare typically taken from an “import” variable domain. Humanization canbe essentially performed following the method of Winter and co-workers[Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature,332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)], bysubstituting rodent CDRs or CDR sequences for the correspondingsequences of a human antibody. Accordingly, such “humanized” antibodiesare chimeric antibodies (U.S. Pat. No. 4,816,567), wherein substantiallyless than an intact human variable domain has been substituted by thecorresponding sequence from a non-human species. In practice, humanizedantibodies are typically human antibodies in which some CDR residues andpossibly some FR residues are substituted by residues from analogoussites in rodent antibodies.

[0627] The choice of human variable domains, both light and heavy, to beused in making the humanized antibodies is very important to reduceantigenicity and HAMA response (human anti-mouse antibody) when theantibody is intended for human therapeutic use. According to theso-called “best-fit” method, the sequence of the variable domain of arodent antibody is screened against the entire library of known humanvariable domain sequences. The human V domain sequence which is closestto that of the rodent is identified and the human framework region (FR)within it accepted for the humanized antibody (Sims et al., J. Immunol.151:2296 (1993); Chothia et al., J. Mol. Biol., 196:901 (1987)). Anothermethod uses a particular framework region derived from the consensussequence of all human antibodies of a particular subgroup of light orheavy chains. The same framework may be used for several differenthumanized antibodies (Carter et al., Proc. Natl. Acad. Sci. USA, 89:4285(1992); Presta et al., J. Immunol. 151:2623 (1993)).

[0628] It is further important that antibodies be humanized withretention of high binding affinity for the antigen and other favorablebiological properties. To achieve this goal, according to a preferredmethod, humanized antibodies are prepared by a process of analysis ofthe parental sequences and various conceptual humanized products usingthree-dimensional models of the parental and humanized sequences.Three-dimensional immunoglobulin models are commonly available and arefamiliar to those skilled in the art. Computer programs are availablewhich illustrate and display probable three-dimensional conformationalstructures of selected candidate immunoglobulin sequences. Inspection ofthese displays permits analysis of the likely role of the residues inthe functioning of the candidate immunoglobulin sequence, i.e., theanalysis of residues that influence the ability of the candidateimmunoglobulin to bind its antigen. In this way, FR residues can beselected and combined from the recipient and import sequences so thatthe desired antibody characteristic, such as increased affinity for thetarget antigen(s), is achieved. In general, the hypervariable regionresidues are directly and most substantially involved in influencingantigen binding.

[0629] Various forms of a humanized anti-TAT antibody are contemplated.For example, the humanized antibody may be an antibody fragment, such asa Fab, which is optionally conjugated with one or more cytotoxicagent(s) in order to generate an immunoconjugate. Alternatively, thehumanized antibody may be an intact antibody, such as an intact IgG1antibody.

[0630] As an alternative to humanization, human antibodies can begenerated. For example, it is now possible to produce transgenic animals(e.g., mice) that are capable, upon immunization, of producing a fullrepertoire of human antibodies in the absence of endogenousimmunoglobulin production. For example, it has been described that thehomozygous deletion of the antibody heavy-chain joining region (J_(H))gene in chimeric and germ-line mutant mice results in completeinhibition of endogenous antibody production. Transfer of the humangerm-line immunoglobulin gene array into such germ-line mutant mice willresult in the production of human antibodies upon antigen challenge.See, e.g., Jakobovits et al., Proc. Natl. Acad. Sci. USA, 90:2551(1993); Jakobovits et al., Nature, 362:255-258 (1993); Bruggemann etal., Year in Immuno. 7:33 (1993); U.S. Pat. Nos. 5,545,806, 5,569,825,5,591,669 (all of GenPharm); 5,545,807; and WO 97/17852.

[0631] Alternatively, phage display technology (McCafferty et al.,Nature 348:552-553 [1990]) can be used to produce human antibodies andantibody fragments in vitro, from immunoglobulin variable (V) domaingene repertoires from unimmunized donors. According to this technique,antibody V domain genes are cloned in-frame into either a major or minorcoat protein gene of a filamentous bacteriophage, such as M13 or fd, anddisplayed as functional antibody fragments on the surface of the phageparticle. Because the filamentous particle contains a single-strandedDNA copy of the phage genome, selections based on the functionalproperties of the antibody also result in selection of the gene encodingthe antibody exhibiting those properties. Thus, the phage mimics some ofthe properties of the B-cell. Phage display can be performed in avariety of formats, reviewed in, e.g., Johnson, Kevin S. and Chiswell,David J., Current Ooinion in Structural Biology 3:564-571 (1993).Several sources of V-gene segments can be used for phage display.Clackson et al., Nature,352:624-628 (1991) isolated a diverse array ofanti-oxazolone antibodies from a small random combinatorial library of Vgenes derived from the spleens of immunized mice. A repertoire of Vgenes from unimmunized human donors can be constructed and antibodies toa diverse array of antigens (including self-antigens) can be isolatedessentially following the techniques described by Marks et al., J. Mol.Biol. 222:581-597 (1991), or Griffith et al., EMBO J. 12:725-734 (1993).See, also, U.S. Pat. Nos. 5,565,332 and 5,573,905.

[0632] As discussed above, human antibodies may also be generated by invitro activated B cells (see U.S. Pat. Nos. 5,567,610 and 5,229,275).

[0633] 4. Antibody Fragments

[0634] In certain circumstances there are advantages of using antibodyfragments, rather than whole antibodies. The smaller size of thefragments allows for rapid clearance, and may lead to improved access tosolid tumors.

[0635] Various techniques have been developed for the production ofantibody fragments. Traditionally, these fragments were derived viaproteolytic digestion of intact antibodies (see, e.g., Morimoto et al.,Journal of Biochemical and Biophysical Methods 24:107-117(1992); andBrennan et al., Science, 229:81 (1985)). However, these fragments cannow be produced directly by recombinant host cells. Fab, Fv and ScFvantibody fragments can all be expressed in and secreted from E. coli,thus allowing the facile production of large amounts of these fragments.Antibody fragments can be isolated from the antibody phage librariesdiscussed above. Alternatively, Fab′-SH fragments can be directlyrecovered from E. coli and chemically coupled to form F(ab′)₂ fragments(Carter et al., Bio/Technology 10:163-167 (1992)). According to anotherapproach, F(ab′)₂ fragments can be isolated directly from recombinanthost cell culture. Fab and F(ab′)₂ fragment with increased in vivohalf-life comprising a salvage receptor binding epitope residues aredescribed in U.S. Pat. No. 5,869,046. Other techniques for theproduction of antibody fragments will be apparent to the skilledpractitioner. In other embodiments, the antibody of choice is a singlechain Fv fragment (scFv). See WO 93/16185; U.S. Pat. No. 5,571,894; andU.S. Pat. No. 5,587,458. Fv and sFv are the only species with intactcombining sites that are devoid of constant regions; thus, they aresuitable for reduced nonspecific binding during in vivo use. sFv fusionproteins may be constructed to yield fusion of an effector protein ateither the amino or the carboxy terminus of an sFv. See AntibodyEngineering, ed. Borrebaeck, supra. The antibody fragment may also be a“linear antibody”, e.g., as described in U.S. Pat. No. 5,641,870 forexample. Such linear antibody fragments may be monospecific orbispecific.

[0636] 5. Bispecific Antibodies

[0637] Bispecific antibodies are antibodies that have bindingspecificities for at least two different epitopes. Exemplary bispecificantibodies may bind to two different epitopes of a TAT protein asdescribed herein. Other such antibodies may combine a TAT binding sitewith a binding site for another protein. Alternatively, an anti-TAT armmay be combined with an arm which binds to a triggering molecule on aleukocyte such as a T-cell receptor molecule (e.g. CD3), or Fc receptorsfor IgG (FcγR), such as FcγRI (CD64), FcγRII (CD32) and FcγRIII (CD16),so as to focus and localize cellular defense mechanisms to theTAT-expressing cell. Bispecific antibodies may also be used to localizecytotoxic agents to cells which express TAT. These antibodies possess aTAT-binding arm and an arm which binds the cytotoxic agent (e.g.,saporin, anti-interferon-α, vinca alkaloid, ricin A chain, methotrexateor radioactive isotope hapten). Bispecific antibodies can be prepared asfull length antibodies or antibody fragments (e.g., F(ab′)₂ bispecificantibodies).

[0638] WO 96/16673 describes a bispecific anti-ErbB2/anti-FcγRIIIantibody and U.S. Pat. No. 5,837,234 discloses a bispecificanti-ErbB2/anti-FcγRI antibody. A bispecific anti-ErbB2/Fc α antibody isshown in WO98/02463. U.S. Pat. No. 5,821,337 teaches a bispecificanti-ErbB2/anti-CD3 antibody.

[0639] Methods for making bispecific antibodies are known in the art.Traditional production of full length bispecific antibodies is based onthe co-expression of two immunoglobulin heavy chain-light chain pairs,where the two chains have different specificities (Millstein et al.,Nature 305:537-539 (1983)). Because of the random assortment ofimmunoglobulin heavy and light chains, these hybridomas (quadromas)produce a potential mixture of 10 different antibody molecules, of whichonly one has the correct bispecific structure. Purification of thecorrect molecule, which is usually done by affinity chromatographysteps, is rather cumbersome, and the product yields are low. Similarprocedures are disclosed in WO 93/08829, and in Traunecker et al., EMBOJ. 10:3655-3659 (1991).

[0640] According to a different approach, antibody variable domains withthe desired binding specificities (antibody-antigen combining sites) arefused to immunoglobulin constant domain sequences. Preferably, thefusion is with an Ig heavy chain constant domain, comprising at leastpart of the hinge, C_(H)2, and C_(H)3 regions. It is preferred to havethe first heavy-chain constant region (C_(H)1) containing the sitenecessary for light chain bonding, present in at least one of thefusions. DNAs encoding the immunoglobulin heavy chain fusions and, ifdesired, the immunoglobulin light chain, are inserted into separateexpression vectors, and are co-transfected into a suitable host cell.This provides for greater flexibility in adjusting the mutualproportions of the three polypeptide fragments in embodiments whenunequal ratios of the three polypeptide chains used in the constructionprovide the optimum yield of the desired bispecific antibody. It is,however, possible to insert the coding sequences for two or all threepolypeptide chains into a single expression vector when the expressionof at least two polypeptide chains in equal ratios results in highyields or when the ratios have no significant affect on the yield of thedesired chain combination.

[0641] In a preferred embodiment of this approach, the bispecificantibodies are composed of a hybrid immunoglobulin heavy chain with afirst binding specificity in one arm, and a hybrid immunoglobulin heavychain-light chain pair (providing a second binding specificity) in theother arm. It was found that this asymmetric structure facilitates theseparation of the desired bispecific compound from unwantedimmunoglobulin chain combinations, as the presence of an immunoglobulinlight chain in only one half of the bispecific molecule provides for afacile way of separation. This approach is disclosed in WO 94/04690. Forfurther details of generating bispecific antibodies see, for example,Suresh et al., Methods in Enzymology 121:210 (1986).

[0642] According to another approach described in U.S. Pat. No.5,731,168, the interface between a pair of antibody molecules can beengineered to maximize the percentage of heterodimers which arerecovered from recombinant cell culture. The preferred interfacecomprises at least a part of the C_(H)3 domain. In this method, one ormore small amino acid side chains from the interface of the firstantibody molecule are replaced with larger side chains (e.g., tyrosineor tryptophan). Compensatory “cavities” of identical or similar size tothe large side chain(s) are created on the interface of the secondantibody molecule by replacing large amino acid side chains with smallerones (e.g., alanine or threonine). This provides a mechanism forincreasing the yield of the heterodimer over other unwanted end-productssuch as homodimers.

[0643] Bispecific antibodies include cross-linked or “heteroconjugate”antibodies. For example, one of the antibodies in the heteroconjugatecan be coupled to avidin, the other to biotin. Such antibodies have, forexample, been proposed to target immune system cells to unwanted cells(U.S. Pat. No.4,676,980), and for treatment of HIV infection (WO91/00360, WO 92/200373, and EP 03089). Heteroconjugate antibodies may bemade using any convenient cross-linking methods. Suitable cross-linkingagents are well known in the art, and are disclosed in U.S. Pat. No.4,676,980, along with a number of cross-linking techniques.

[0644] Techniques for generating bispecific antibodies from antibodyfragments have also been described in the literature. For example,bispecific antibodies can be prepared using chemical linkage. Brennan etal., Science 229:81 (1985) describe a procedure wherein intactantibodies are proteolytically cleaved to generate F(ab′)₂ fragments.These fragments are reduced in the presence of the dithiol complexingagent, sodium arsenite, to stabilize vicinal dithiols and preventintermolecular disulfide formation. The Fab′ fragments generated arethen converted to thionitrobenzoate (TNB) derivatives. One of theFab′-TNB derivatives is then reconverted to the Fab′-thiol by reductionwith mercaptoethylamine and is mixed with an equimolar amount of theother Fab′-TNB derivative to form the bispecific antibody. Thebispecific antibodies produced can be used as agents for the selectiveimmobilization of enzymes.

[0645] Recent progress has facilitated the direct recovery of Fab′-SHfragments from E. coli, which can be chemically coupled to formbispecific antibodies. Shalaby et al.,J. Exp. Med. 175: 217-225 (1992)describe the production of a fully humanized bispecific antibody F(ab′)₂molecule. Each Fab′ fragment was separately secreted from E. coli andsubjected to directed chemical coupling in vitro to form the bispecificantibody. The bispecific antibody thus formed was able to bind to cellsoverexpressing the ErbB2 receptor and normal human T cells, as well astrigger the lytic activity of human cytotoxic lymphocytes against humanbreast tumor targets. Various techniques for making and isolatingbispecific antibody fragments directly from recombinant cell culturehave also been described. For example, bispecific antibodies have beenproduced using leucine zippers. Kostelny et al., J. Immunol.148(5):1547-1553 (1992). The leucine zipper peptides from the Fos andJun proteins were linked to the Fab′ portions of two differentantibodies by gene fusion. The antibody homodimers were reduced at thehinge region to form monomers and then re-oxidized to form the antibodyheterodimers. This method can also be utilized for the production ofantibody homodimers. The “diabody” technology described by Hollinger etal., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993) has provided analternative mechanism for making bispecific antibody fragments. Thefragments comprise a V_(H) connected to a V_(L) by a linker which is tooshort to allow pairing between the two domains on the same chain.Accordingly, the V_(H) and V_(L) domains of one fragment are forced topair with the complementary V_(L) and V_(H) domains of another fragment,thereby forming two antigen-binding sites. Another strategy for makingbispecific antibody fragments by the use of single-chain Fv (sFv) dimershas also been reported. See Gruber et al., J. Immunol., 152:5368 (1994).

[0646] Antibodies with more than two valencies are contemplated. Forexample, trispecific antibodies can be prepared. Tutt et al., J.Immunol. 147:60 (1991).

[0647] 6. Heteroconjugate Antibodies

[0648] Heteroconjugate antibodies are also within the scope of thepresent invention. Heteroconjugate antibodies are composed of twocovalently joined antibodies. Such antibodies have, for example, beenproposed to target immune system cells to unwanted cells [U.S. Pat. No.4,676,980], and for treatment of HIV infection [WO 91/00360; WO92/200373; EP 03089]. It is contemplated that the antibodies may beprepared in vitro using known methods in synthetic protein chemistry,including those involving crosslinking agents. For example, immunotoxinsmay be constructed using a disulfide exchange reaction or by forming athioether bond. Examples of suitable reagents for this purpose includeiminothiolate and methyl4-mercaptobutyrimidate and those disclosed, forexample, in U.S. Pat. No. 4,676,980.

[0649] 7. Multivalent Antibodies

[0650] A multivalent antibody may be internalized (and/or catabolized)faster than a bivalent antibody by a cell expressing an antigen to whichthe antibodies bind. The antibodies of the present invention can bemultivalent antibodies (which are other than of the IgM class) withthree or more antigen binding sites (e.g. tetravalent antibodies), whichcan be readily produced by recombinant expression of nucleic acidencoding the polypeptide chains of the antibody. The multivalentantibody can comprise a dimerization domain and three or more antigenbinding sites. The preferred dimerization domain comprises (or consistsof) an Fc region or a hinge region. In this scenario, the antibody willcomprise an Fc region and three or more antigen binding sitesamino-terminal to the Fc region. The preferred multivalent antibodyherein comprises (or consists of) three to about eight, but preferablyfour, antigen binding sites. The multivalent antibody comprises at leastone polypeptide chain (and preferably two polypeptide chains), whereinthe polypeptide chain(s) comprise two or more variable domains. Forinstance, the polypeptide chain(s) may compriseVD1-(X1)_(n)-VD2-(X2)_(n)-Fc, wherein VD1 is a first variable domain,VD2 is a second variable domain, Fc is one polypeptide chain of an Fcregion, X1 and X2 represent an amino acid or polypeptide, and n is 0or 1. For instance, the polypeptide chain(s) may comprise:VH—CH1-flexible linker-VH—CH1-Fc region chain; or VH—CH1-VH—CH1-Fcregion chain. The multivalent antibody herein preferably furthercomprises at least two (and preferably four) light chain variable domainpolypeptides. The multivalent antibody herein may, for instance,comprise from about two to about eight light chain variable domainpolypeptides. The light chain variable domain polypeptides contemplatedhere comprise a light chain variable domain and, optionally, furthercomprise a CL domain.

[0651] 8. Effector Function Engineering

[0652] It may be desirable to modify the antibody of the invention withrespect to effector function, e.g., so as to enhance antigen-dependentcell-mediated cyotoxicity (ADCC) and/or complement dependentcytotoxicity (CDC) of the antibody. This may be achieved by introducingone or more amino acid substitutions in an Fc region of the antibody.Alternatively or additionally, cysteine residue(s) may be introduced inthe Fc region, thereby allowing interchain disulfide bond formation inthis region. The homodimeric antibody thus generated may have improvedinternalization capability and/or increased complement-mediated cellkilling and antibody-dependent cellular cytotoxicity (ADCC). See Caronet al., J. Exp Med. 176:1191-1195 (1992) and Shopes, B. J. Immunol.148:2918-2922 (1992). Homodimeric antibodies with enhanced anti-tumoractivity may also be prepared using heterobifunctional cross-linkers asdescribed in Wolffet al., Cancer Research 53:2560-2565 (1993).Alternatively, an antibody can be engineered which has dual Fc regionsand may thereby have enhanced complement lysis and ADCC capabilities.See Stevenson et al., Anti-Cancer Drug Design 3:219-230 (1989). Toincrease the serum half life of the antibody, one may incorporate asalvage receptor binding epitope into the antibody (especially anantibody fragment) as described in U.S. Pat. No. 5,739,277, for example.As used herein, the term “salvage receptor binding epitope” refers to anepitope of the Fc region of an IgG molecule (e.g., IgG₁, IgG₂, IgG₃, orIgG₄) that is responsible for increasing the in vivo serum half-life ofthe IgG molecule.

[0653] 9. Immunoconjugates

[0654] The invention also pertains to immunoconjugates comprising anantibody conjugated to a cytotoxic agent such as a chemotherapeuticagent, a growth inhibitory agent, a toxin (e.g., an enzymatically activetoxin of bacterial, fungal, plant, or animal origin, or fragmentsthereof), or a radioactive isotope (i.e., a radioconjugate).

[0655] Chemotherapeutic agents useful in the generation of suchimmunoconjugates have been described above. Enzymatically active toxinsand fragments thereof that can be used include diphtheria A chain,nonbinding active fragments of diphtheria toxin, exotoxin A chain (fromPseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain,alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolacaamericana proteins (PAPI, PAPII, and PAP-S), momordica charantiainhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin,mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. Avariety of radionuclides are available for the production ofradioconjugated antibodies. Examples include ²¹²Bi, ¹³¹I, ¹³¹In, ⁹⁰Y,and ¹⁸⁶Re. Conjugates of the antibody and cytotoxic agent are made usinga variety of bifunctional protein-coupling agents such asN-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP), iminothiolane(IT), bifunctional derivatives of imidoesters (such as dimethyladipimidate HCL), active esters (such as disuccinimidyl suberate),aldehydes (such as glutareldehyde), bis-azido compounds (such as his(p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such asbis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such astolyene 2,6-diisocyanate), and his-active fluorine compounds (such as1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin canbe prepared as described in Vitetta et al., Science, 238: 1098 (1987).Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent forconjugation of radionucleotide to the antibody. See WO94/11026.

[0656] Conjugates of an antibody and one or more small molecule toxins,such as a calicheamicin, maytansinoids, a trichothene, and CC1065, andthe derivatives of these toxins that have toxin activity, are alsocontemplated herein.

[0657] Maytansine and Maytansinoids

[0658] In one preferred embodiment, an anti-TAT antibody (full length orfragments) of the invention is conjugated to one or more maytansinoidmolecules.

[0659] Maytansinoids are mitototic inhibitors which act by inhibitingtubulin polymerization. Maytansine was first isolated from the eastAfrican shrub Maytenius serrata (U.S. Pat. No. 3,896,111). Subsequently,it was discovered that certain microbes also produce maytansinoids, suchas maytansinol and C-3 maytansinol esters (U.S. Pat. No. 4,151,042).Synthetic maytansinol and derivatives and analogues thereof aredisclosed, for example, in U.S. Pat. Nos. 4,137,230; 4,248,870;4,256,746; 4,260,608; 4,265,814; 4,294,757; 4,307,016; 4,308,268;4,308,269; 4,309,428; 4,313,946; 4,315,929; 4,317,821; 4,322,348;4,331,598; 4,361,650; 4,364,866; 4,424,219; 4,450,254; 4,362,663; and4,371,533, the disclosures of which are hereby expressly incorporated byreference.

[0660] Maytansinoid-Antibody Conjugates

[0661] In an attempt to improve their therapeutic index, maytansine andmaytansinoids have been conjugated to antibodies specifically binding totumor cell antigens. Immunoconjugates containing maytansinoids and theirtherapeutic use are disclosed, for example, in U.S. Pat. Nos. 5,208,020,5,416,064 and European Patent EP 0 425 235 B1, the disclosures of whichare hereby expressly incorporated by reference. Liu et al.,Proc. Natl.Acad. Sci. USA 93:8618-8623 (1996) described immunoconjugates comprisinga maytansinoid designated DM1 linked to the monoclonal antibody C242directed against human colorectal cancer. The conjugate was found to behighly cytotoxic towards cultured colon cancer cells, and showedantitumor activity in an in vivo tumor growth assay. Chari et al.,Cancer Research 52:127-131 (1992) describe immunoconjugates in which amaytansinoid was conjugated via a disulfide linker to the murineantibody A7 binding to an antigen on human colon cancer cell lines, orto another murine monoclonal antibody TA.1 that binds the HER-2/neuoncogene. The cytotoxicity of the TA.1-maytansonoid conjugate was testedin vitro on the human breast cancer cell line SK-BR-3, which expresses3×10⁵ HER-2 surface antigens per cell. The drug conjugate achieved adegree of cytotoxicity similar to the free maytansonid drug, which couldbe increased by increasing the number of maytansinoid molecules perantibody molecule. The A7-maytansinoid conjugate showed low systemiccytotoxicity in mice.

[0662] Anti-TAT Polypeptide Antibody-Maytansinoid Conjugates(Immunoconjugates)

[0663] Anti-TAT antibody-maytansinoid conjugates are prepared bychemically linking an anti-TAT antibody to a maytansinoid moleculewithout significantly diminishing the biological activity of either theantibody or the maytansinoid molecule. An average of 3-4 maytansinoidmolecules conjugated per antibody molecule has shown efficacy inenhancing cytotoxicity of target cells without negatively affecting thefunction or solubility of the antibody, although even one molecule oftoxin/antibody would be expected to enhance cytotoxicity over the use ofnaked antibody. Maytansinoids are well known in the art and can besynthesized by known techniques or isolated from natural sources.Suitable maytansinoids are disclosed, for example, in U.S. Pat. No.5,208,020 and in the other patents and nonpatent publications referredto hereinabove. Preferred maytansinoids are maytansinol and maytansinolanalogues modified in the aromatic ring or at other positions of themaytansinol molecule, such as various maytansinol esters.

[0664] There are many linking groups known in the art for makingantibody-maytansinoid conjugates, including, for example, thosedisclosed in U.S. Pat. No. 5,208,020 or EP Patent 0 425 235 B1, andChari et al., Cancer Research 52:127-131 (1992). The linking groupsinclude disufide groups, thioether groups, acid labile groups,photolabile groups, peptidase labile groups, or esterase labile groups,as disclosed in the above-identified patents, disulfide and thioethergroups being preferred.

[0665] Conjugates of the antibody and maytansinoid may be made using avariety of bifunctional protein coupling agents such asN-succinimidyl-3-(2-pyridyidithio) propionate (SPDP),succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate,iminothiolane (IT), bifunctional derivatives of imidoesters (such asdimethyl adipimidate HCL), active esters (such as disuccinimidylsuberate), aldehydes (such as glutareldehyde), bis-azido compounds (suchas bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (suchas bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such astoluene 2,6-diisocyanate), and bis-active fluorine compounds (such as1,5-difluoro-2,4-dinitrobenzene). Particularly preferred coupling agentsinclude N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP) (Carlssonet al., Biochem. J. 173:723-737 [1978]) andN-succinimidyl-4-(2-pyridylthio)pentanoate (SPP) to provide for adisulfide linkage.

[0666] The linker may be attached to the maytansinoid molecule atvarious positions, depending on the type of the link. For example, anester linkage may be formed by reaction with a hydroxyl group usingconventional coupling techniques. The reaction may occur at the C-3position having a hydroxyl group, the C-14 position modified withhyrdoxymethyl, the C-15 position modified with a hydroxyl group, and theC-20 position having a hydroxyl group. In a preferred embodiment, thelinkage is formed at the C-3 position of maytansinol or a maytansinolanalogue.

[0667] Calicheamicin

[0668] Another immunoconjugate of interest comprises an anti-TATantibody conjugated to one or more calicheamicin molecules. Thecalicheamicin family of antibiotics are capable of producingdouble-stranded DNA breaks at sub-picomolar concentrations. For thepreparation of conjugates of the calicheamicin family, see U.S. Pat.Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710,5,773,001, 5,877,296 (all to American Cyanamid Company). Structuralanalogues of calicheamicin which may be used include, but are notlimited to, γ₁ ^(I), α₂ ^(I), α₃ ^(I), N-acetyl-γ₁ ^(I), PSAG and θ^(I)₁ (Hinman et al., Cancer Research 53:3336-3342 (1993), Lode et al.,Cancer Research 58:2925-2928 (1998) and the aforementioned U.S. patentsto American Cyanamid). Another anti-tumor drug that the antibody can beconjugated is QFA which is an antifolate. Both calicheamicin and QFAhave intracellular sites of action and do not readilycross the plasmamembrane. Therefore, cellular uptake of these agents through antibodymediated internalization greatly enhances their cytotoxic effects.

[0669] Other Cytotoxic Agents

[0670] Other antitumor agents that can be conjugated to the anti-TATantibodies of the invention include BCNU, streptozoicin, vincristine and5-fluorouracil, the family of agents known collectively LL-E33288complex described in U.S. Pat. Nos. 5,053,394, 5,770,710, as well asesperamicins (U.S. Pat. No. 5,877,296).

[0671] Enzymatically active toxins and fragments thereof which can beused include diphtheria A chain, nonbinding active fragments ofdiphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricinA chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordiiproteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII,and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonariaofficinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin,enomycin and the tricothecenes. See, for example, WO 93/21232 publishedOct. 28, 1993.

[0672] The present invention further contemplates an immunoconjugateformed between an antibody and a compound with nucleolytic activity(e.g., a ribonuclease or a DNA endonuclease such as a deoxyribonuclease;DNase).

[0673] For selective destruction of the tumor, the antibody may comprisea highly radioactive atom. A variety of radioactive isotopes areavailable for the production of radioconjugated anti-TAT antibodies.Examples include At²¹¹, I¹³¹, I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹²,P³², Pb²¹² and radioactive isotopes of Lu. When the conjugate is usedfor diagnosis, it may comprise a radioactive atom for scintigraphicstudies, for example tc^(99m) or I¹²³, or a spin label for nuclearmagnetic resonance (NMR) imaging (also known as magnetic resonanceimaging, mri), such as iodine-123 again, iodine-131, indium-111,fluorine-19, carbon-13, nitrogen-15, oxygen-17, ga or iron.

[0674] The radio- or other labels may be incorporated in the conjugatein known ways. For example, the peptide may be biosynthesized or may besynthesized by chemical amino acid synthesis using suitable amino acidprecursors involving, for example, fluorine-19 in place of hydrogen.Labels such as tc^(99m) or I¹²³, .Re¹⁸⁶, Re¹⁸⁸ and In¹¹¹ can be attachedvia a cysteine residue in the peptide. Yttrium-90 can be attached via alysine residue. The IODOGEN method (Fraker et al (1978) Biochem.Biophys. Res. Commun. 80: 49-57 can be used to incorporate iodine-123.“Monoclonal Antibodies in Immunoscintigraphy” (Chatal,CRC Press 1989)describes other methods in detail.

[0675] Conjugates of the antibody and cytotoxic agent may be made usinga variety of bifunctional protein coupling agents such asN-succinimidyl-3-(2-pyridyldithio) propionate (SPDP),succinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate,iminothiolane (IT), bifunctional derivatives of imidoesters (such asdimethyl adipimidate HCL), active esters (such as disuccinimidylsuberate), aldehydes (such as glutareldehyde), bis-azido compounds (suchas bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (suchas bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such astolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin canbe prepared as described in Vitetta et al., Science 238:1098 (1987).Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent forconjugation of radionucleotide to the antibody. See WO94/11026. Thelinker may be a “cleavable linker” facilitating release of the cytotoxicdrug in the cell. For example, an acid-labile linker,peptidase-sensitive linker, photolabile linker, dimethyl linker ordisulfide-containing linker (Chari et al., Cancer Research 52:127-131(1992); U.S. Pat. No. 5,208,020) may be used.

[0676] Alternatively, a fusion protein comprising the anti-TAT antibodyand cytotoxic agent may be made, e.g., by recombinant techniques orpeptide synthesis. The length of DNA may comprise respective regionsencoding the two portions of the conjugate either adjacent one anotheror separated by a region encoding a linker peptide which does notdestroy the desired properties of the conjugate.

[0677] In yet another embodiment, the antibody may be conjugated to a“receptor” (such streptavidin) for utilization in tumor pre-targetingwherein the antibody-receptor conjugate is administered to the patient,followed by removal of unbound conjugate from the circulation using aclearing agent and then administration of a “ligand” (e.g., avidin)which is conjugated to a cytotoxic agent (e.g., a radionucleotide).

[0678] 10. Immunoliposomes

[0679] The anti-TAT antibodies disclosed herein may also be formulatedas immunoliposomes. A “liposome” is a small vesicle composed of varioustypes of lipids, phospholipids and/or surfactant which is useful fordelivery of a drug to a mammal. The components of the liposome arecommonly arranged in a bilayer formation, similar to the lipidarrangement of biological membranes. Liposomes containing the antibodyare prepared by methods known in the art, such as described in Epsteinet al., Proc. Natl. Acad. Sci. USA 82:3688 (1985); Hwang et al., Proc.Natl. Acad. Sci. USA77:4030 (1980); U.S. Pat. Nos. 4,485,045 and4,544,545; and WO97/38731 published Oct. 23, 1997. Liposomes withenhanced circulation time are disclosed in U.S. Pat. No. 5,013,556.

[0680] Particularly useful liposomes can be generated by the reversephase evaporation method with a lipid composition comprisingphosphatidylcholine, cholesterol and PEG-derivatizedphosphatidylethanolamine (PEG-PE). Liposomes are extruded throughfilters of defined pore size to yield liposomes with the desireddiameter. Fab′ fragments of the antibody of the present invention can beconjugated to the liposomes as described in Martin et al., J. Biol.Chem. 257:286-288 (1982) via a disulfide interchange reaction. Achemotherapeutic agent is optionally contained within the liposome. SeeGabizon et al., J. National Cancer Inst. 81(19):1484 (1989).

[0681] B. TAT Binding Oligopeptides

[0682] TAT binding oligopeptides of the present invention areoligopeptides that bind, preferably specifically, to a TAT polypeptideas described herein. TAT binding oligopeptides may be chemicallysynthesized using known oligopeptide synthesis methodology or may beprepared and purified using recombinant technology. TAT bindingoligopeptides are usually at least about 5 amino acids in length,alternatively at least about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 amino acids in length ormore, wherein such oligopeptides that are capable of binding, preferablyspecifically, to a TAT polypeptide as described herein. TAT bindingoligopeptides may be identified without undue experimentation using wellknown techniques. In this regard, it is noted that techniques forscreening oligopeptide libraries for oligopeptides that are capable ofspecifically binding to a polypeptide target are well known in the art(see, e.g., U.S. Pat. Nos. 5,556,762, 5,750,373, 4,708,871, 4,833,092,5,223,409, 5,403,484, 5,571,689, 5,663,143; PCT Publication Nos. WO84/03506 and WO84/03564; Geysen et al., Proc. Natl. Acad. Sci. U.S.A.,81:3998-4002 (1984); Geysen et al., Proc. Natl. Acad. Sci. U.S.A.,82:178-182 (1985); Geysen et al., in Synthetic Peptides as Antigens,130-149 (1986); Geysen et al., J. Immunol. Meth., 102:259-274 (1987);Schoofs et al., J. Immunol., 140:611-616 (1988), Cwirla, S. E. et al.(1990) Proc. Natl. Acad. Sci. USA, 87:6378; Lowman, H. B. et al. (1991)Biochemistry, 30:10832; Clackson, T. et al. (1991) Nature, 352: 624;Marks, J. D. et al. (1991), J. Mol. Biol., 222:581; Kang, A. S. et al.(1991) Proc. Natl. Acad. Sci. USA, 88:8363, and Smith, G. P. (1991)Current Opin. Biotechnol., 2:668).

[0683] In this regard, bacteriophage (phage) display is one well knowntechnique which allows one to screen large oligopeptide libraries toidentify member(s) of those libraries which are capable of specificallybinding to a polypeptide target. Phage display is a technique by whichvariant polypeptides are displayed as fusion proteins to the coatprotein on the surface of bacteriophage particles (Scott, J. K. andSmith, G. P. (1990) Science 249: 386).

[0684] The utility of phage display lies in the fact that largelibraries of selectively randomized protein variants (or randomly clonedcDNAs) can be rapidly and efficiently sorted for those sequences thatbind to a target molecule with high affinity. Display of peptide(Cwirla, S. E. et al. (1990) Proc. Nat]. Acad. Sci. USA, 87:6378) orprotein (Lowman, H. B. et al. (1991) Biochemistry, 30:10832; Clackson,T. et al. (1991) Nature, 352: 624; Marks, J. D. et al. (1991), J. Mol.Biol., 222:581; Kang, A. S. et al. (1991) Proc. Natl. Acad. Sci. USA,88:8363) libraries on phage have been used for screening millions ofpolypeptides or oligopeptides for ones with specific binding properties(Smith, G. P. (1991) Current Opin. Biotechnol., 2:668). Sorting phagelibraries of random mutants requires a strategy for constructing andpropagating a large number of variants, a procedure for affinitypurification using the target receptor, and a means of evaluating theresults of binding enrichments. U.S. Pat. Nos. 5,223,409, 5,403,484,5,571,689, and 5,663,143.

[0685] Although most phage display methods have used filamentous phage,lambdoid phage display systems (WO 95/34683; U.S. Pat. No. 5,627,024),T4 phage display systems (Ren, Z-J. et al. (1998) Gene 215:439; Zhu, Z.(1997) CAN 33:534; Jiang, J. et al. (1997) can 128:44380; Ren, Z-J. etal. (1997) CAN 127:215644; Ren, Z-J. (1996) Protein Sci. 5:1833; Efimov,V. P. et al. (1995) Virus Genes 10:173) and T7 phage display systems(Smith, G. P. and Scott, J. K. (1993) Methods in Enzymology, 217,228-257; U.S. Pat. No. 5,766,905) are also known.

[0686] Many other improvements and variations of the basic phage displayconcept have now been developed. These improvements enhance the abilityof display systems to screen peptide libraries for binding to selectedtarget molecules and to display functional proteins with the potentialof screening these proteins for desired properties. Combinatorialreaction devices for phage display reactions have been developed (WO98/14277) and phage display libraries have been used to analyze andcontrol bimolecular interactions (WO 98/20169; WO 98/20159) andproperties of constrained helical peptides (WO 98/20036). WO 97/35196describes a method of isolating an affinity ligand in which a phagedisplay library is contacted with one solution in which the ligand willbind to a target molecule and a second solution in which the affinityligand will not bind to the target molecule, to selectively isolatebinding ligands. WO 97/46251 describes a method of biopanning a randomphage display library with an affinity purified antibody and thenisolating binding phage, followed by a micropanning process usingmicroplate wells to isolate high affinity binding phage. The use ofStaphlylococcus aureus protein A as an affinity tag has also beenreported (Li et al. (1998) Mol Biotech., 9:187). WO 97/47314 describesthe use of substrate subtraction libraries to distinguish enzymespecificities using a combinatorial library which may be a phage displaylibrary. A method for selecting enzymes suitable for use in detergentsusing phage display is described in WO 97/09446. Additional methods ofselecting specific binding proteins are described in U.S. Pat. Nos.5,498,538, 5,432,018, and WO 98/15833.

[0687] Methods of generating peptide libraries and screening theselibraries are also disclosed in U.S. Pat. Nos. 5,723,286, 5,432,018,5,580,717, 5,427,908, 5,498,530, 5,770,434, 5,734,018, 5,698,426,5,763,192, and 5,723,323.

[0688] C. TAT Binding Organic Molecules

[0689] TAT binding organic molecules are organic molecules other thanoligopeptides or antibodies as defined herein that bind, preferablyspecifically, to a TAT polypeptide as described herein. TAT bindingorganic molecules may be identified and chemically synthesized usingknown methodology (see, e.g., PCT Publication Nos. WO00/00823 andWO00/39585). TAT binding organic molecules are usually less than about2000 daltons in size, alternatively less than about 1500, 750, 500, 250or 200 daltons in size, wherein such organic molecules that are capableof binding, preferably specifically, to a TAT polypeptide as describedherein may be identified without undue experimentation using well knowntechniques. In this regard, it is noted that techniques for screeningorganic molecule libraries for molecules that are capable of binding toa polypeptide target are well known in the art (see, e.g., PCTPublication Nos. WO00/00823 and WO00/39585). TAT binding organicmolecules may be, for example, aldehydes, ketones, oximes, hydrazones,semicarbazones, carbazides, primary amines, secondary amines, tertiaryamines, N-substituted hydrazines, hydrazides, alcohols, ethers, thiols,thioethers, disulfides, carboxylic acids, esters, amides, ureas,carbamates, carbonates, ketals, thioketals, acetals, thioacetals, arylhalides, aryl sulfonates, alkyl halides, alkyl sulfonates, aromaticcompounds, heterocyclic compounds, anilines, alkenes, alkynes, diols,amino alcohols, oxazolidines, oxazolines, thiazolidines, thiazolines,enamines, sulfonamides, epoxides, aziridines, isocyanates, sulfonylchlorides, diazo compounds, acid chlorides, or the like.

[0690] D. Screening for Anti-TAT Antibodies, TAT Binding Oligopeptidesand TAT Binding Organic Molecules with the Desired Properties

[0691] Techniques for generating antibodies, oligopeptides and organicmolecules that bind to TAT polypeptides have been described above. Onemay further select antibodies, oligopeptides or other organic moleculeswith certain biological characteristics, as desired.

[0692] The growth inhibitory effects of an anti-TAT antibody,oligopeptide or other organic molecule of the invention may be assessedby methods known in the art, e.g., using cells which express a TATpolypeptide either endogenously or following transfection with the TATgene. For example, appropriate tumor cell lines and TAT-transfectedcells may treated with an anti-TAT monoclonal antibody, oligopeptide orother organic molecule of the invention at various concentrations for afew days (e.g., 2-7) days and stained with crystal violet or MTT oranalyzed by some other colorimetric assay. Another method of measuringproliferation would be by comparing ³H-thymidine uptake by the cellstreated in the presence or absence an anti-TAT antibody, TAT bindingoligopeptide or TAT binding organic molecule of the invention. Aftertreatment, the cells are harvested and the amount of radioactivityincorporated into the DNA quantitated in a scintillation counter.Appropriate positive controls include treatment of a selected cell linewith a growth inhibitory antibody known to inhibit growth of that cellline. Growth inhibition of tumor cellsin vivo can be determined invarious ways known in the art. Preferably, the tumor cell is one thatoverexpresses a TAT polypeptide. Preferably, the anti-TAT antibody, TATbinding oligopeptide or TAT binding organic molecule will inhibit cellproliferation of a TAT-expressing tumor cell in vitro or in vivo byabout 25-100% compared to the untreated tumor cell, more preferably, byabout 30-100%, and even more preferably by about 50-100% or 70-100%, inone embodiment, at an antibody concentration of about 0.5 to 30 μg/ml.Growth inhibition can be measured at an antibody concentration of about0.5 to

/ml or about 0.5 nM to 200 nM in cell culture, where the growthinhibition is determined 1-10 days after exposure of the tumor cells tothe antibody. The antibody is growth inhibitoryn vivo if administrationof the anti-TAT antibody at about 1 μg/kg to about 100 mg/kg body weightresults in reduction in tumor size or reduction of tumor cellproliferation within about 5 days to 3 months from the firstadministration of the antibody, preferably within about 5 to 30 days.

[0693] To select for an anti-TAT antibody, TAT binding oligopeptide orTAT binding organic molecule which induces cell death, loss of membraneintegrity as indicated by, e.g., propidium iodide (PI), trypan blue or7AAD uptake may be assessed relative to control. A PI uptake assay canbe performed in the absence of complement and immune effector cells. TATpolypeptide-expressing tumor cells are incubated with medium alone ormedium containing the appropriate anti-TAT antibody (e.g, at about 10μg/ml), TAT binding oligopeptide or TAT binding organic molecule. Thecells are incubated for a 3 day time period. Following each treatment,cells are washed and aliquoted into 35 mm strainer-capped 12×75 tubes (1ml per tube, 3 tubes per treatment group) for removal of cell clumps.Tubes then receive PI (10 μg/ml). Samples may be analyzed using aFACSCAN® flow cytometer and FACSCONVERT® CellQuest software (BectonDickinson). Those anti-TAT antibodies, TAT binding oligopeptides or TATbinding organic molecules that induce statistically significant levelsof cell death as determined by PI uptake may be selected as celldeath-inducing anti-TAT antibodies, TAT binding oligopeptides or TATbinding organic molecules.

[0694] To screen for antibodies, oligopeptides or other organicmolecules which bind to an epitope on a TAT polypeptide bound by anantibody of interest, a routine cross-blocking assay such as thatdescribed in Antibodies, A Laboratory Manual, Cold Spring HarborLaboratory, Ed Harlow and David Lane (1988), can be performed. Thisassay can be used to determine if a test antibody, oligopeptide or otherorganic molecule binds the same site or epitope as a known anti-TATantibody. Alternatively, or additionally, epitope mapping can beperformed by methods known in the art. For example, the antibodysequence can be mutagenized such as by alanine scanning, to identifycontact residues. The mutant antibody is initailly tested for bindingwith polyclonal antibody to ensure proper folding. In a differentmethod, peptides corresponding to different regions of a TAT polypeptidecan be used in competition assays with the test antibodies or with atest antibody and an antibody with a characterized or known epitope.

[0695] E. Antibody Dependent Enzyme Mediated Prodrug Therapy (ADEPT)

[0696] The antibodies of the present invention may also be used in ADEPTby conjugating the antibody to a prodrug-activating enzyme whichconverts a prodrug (e.g., a peptidyl chemotherapeutic agent, seeWO81/01145) to an active anti-cancer drug. See, for example, WO 88/07378and U.S. Pat. No. 4,975,278.

[0697] The enzyme component of the immunoconjugate useful for ADEPTincludes any enzyme capable of acting on a prodrug in such a way so asto covert it into its more active, cytotoxic form.

[0698] Enzymes that are useful in the method of this invention include,but are not limited to, alkaline phosphatase useful for convertingphosphate-containing prodrugs into free drugs; arylsulfatase useful forconverting sulfate-containing prodrugs into free drugs; cytosinedeaminase useful for converting non-toxic 5-fluorocytosine into theanti-cancer drug, 5-fluorouracil; proteases, such as serratia protease,thermolysin, subtilisin, carboxypeptidases and cathepsins (such ascathepsins B and L), that are useful for converting peptide-containingprodrugs into free drugs; D-alanylcarboxypeptidases, useful forconverting prodrugs that contain D-amino acid substituents;carbohydrate-cleaving enzymes such as β-galactosidase and neuraminidaseuseful for converting glycosylated prodrugs into free drugs; β-lactamaseuseful for converting drugs derivatized with β-lactams into free drugs;and penicillin amidases, such as penicillin V amidase or penicillin Gamidase, useful for converting drugs derivatized at their aminenitrogens with phenoxyacetyl or phenylacetyl groups, respectively, intofree drugs. Alternatively, antibodies with enzymatic activity, alsoknown in the art as “abzymes”, can be used to convert the prodrugs ofthe invention into free active drugs (see, e.g., Massey, Nature328:457-458 (1987)). Antibody-abzyme conjugates can be prepared asdescribed herein for delivery of the abzyme to a tumor cell population.

[0699] The enzymes of this invention can be covalently bound to theanti-TAT antibodies by techniques well known in the art such as the useof the heterobifunctional crosslinking reagents discussed above.Alternatively, fusion proteins comprising at least the antigen bindingregion of an antibody of the invention linked to at least a functionallyactive portion of an enzyme of the invention can be constructed usingrecombinant DNA techniques well known in the art (see, e.g., Neubergeret al., Nature 312:604-608 (1984).

[0700] F. Full-Length TAT Polypeptides

[0701] The present invention also provides newly identified and isolatednucleotide sequences encoding polypeptides referred to in the presentapplication as TAT polypeptides. In particular, cDNAs (partial andfull-length) encoding various TAT polypeptides have been identified andisolated, as disclosed in further detail in the Examples below.

[0702] As disclosed in the Examples below, various cDNA clones have beendeposited with the ATCC. The actual nucleotide sequences of those clonescan readily be determined by the skilled artisan by sequencing of thedeposited clone using routine methods in the art. The predicted aminoacid sequence can be determined from the nucleotide sequence usingroutine skill. For the TAT polypeptides and encoding nucleic acidsdescribed herein, in some cases, Applicants have identified what isbelieved to be the reading frame best identifiable with the sequenceinformation available at the time.

[0703] G. Anti-TAT Antibody and TAT Polypeptide Variants

[0704] In addition to the anti-TAT antibodies and full-length nativesequence TAT polypeptides described herein, it is contemplated thatanti-TAT antibody and TAT polypeptide variants can be prepared. Anti-TATantibody and TAT polypeptide variants can be prepared by introducingappropriate nucleotide changes into the encoding DNA, and/or bysynthesis of the desired antibody or polypeptide. Those skilled in theart will appreciate that amino acid changes may alter post-translationalprocesses of the anti-TAT antibody or TAT polypeptide, such as changingthe number or position of glycosylation sites or altering the membraneanchoring characteristics.

[0705] Variations in the anti-TAT antibodies and TAT polypeptidesdescribed herein, can be made, for example, using any of the techniquesand guidelines for conservative and non-conservative mutations setforth, for instance, in U.S. Pat. No. 5,364,934. Variations may be asubstitution, deletion or insertion of one or more codons encoding theantibody or polypeptide that results in a change in the amino acidsequence as compared with the native sequence antibody or polypeptide.Optionally the variation is by substitution of at least one amino acidwith any other amino acid in one or more of the domains of the anti-TATantibody or TAT polypeptide. Guidance in determining which amino acidresidue may be inserted, substituted or deleted without adverselyaffecting the desired activity may be found by comparing the sequence ofthe anti-TAT antibody or TAT polypeptide with that of homologous knownprotein molecules and minimizing the number of amino acid sequencechanges made in regions of high homology. Amino acid substitutions canbe the result of replacing one amino acid with another amino acid havingsimilar structural and/or chemical properties, such as the replacementof a leucine with a serine, i.e., conservative amino acid replacements.Insertions or deletions may optionally be in the range of about 1 to 5amino acids. The variation allowed may be determined by systematicallymaking insertions, deletions or substitutions of amino acids in thesequence and testing the resulting variants for activity exhibited bythe full-length or mature native sequence.

[0706] Anti-TAT antibody and TAT polypeptide fragments are providedherein. Such fragments may be truncated at the N-terminus or C-terminus,or may lack internal residues, for example, when compared with a fulllength native antibody or protein. Certain fragments lack amino acidresidues that are not essential for a desired biological activity of theanti-TAT antibody or TAT polypeptide.

[0707] Anti-TAT antibody and TAT polypeptide fragments may be preparedby any of a number of conventional techniques. Desired peptide fragmentsmay be chemically synthesized. An alternative approach involvesgenerating antibody or polypeptide fragments by enzymatic digestion,e.g., by treating the protein with an enzyme known to cleave proteins atsites defined by particular amino acid residues, or by digesting the DNAwith suitable restriction enzymes and isolating the desired fragment.Yet another suitable technique involves isolating and amplifying a DNAfragment encoding a desired antibody or polypeptide fragment, bypolymerase chain reaction (PCR). Oligonucleotides that define thedesired termini of the DNA fragment are employed at the 5′ and 3′primers in the PCR. Preferably, anti-TAT antibody and TAT polypeptidefragments share at least one biological and/or immunological activitywith the native anti-TAT antibody or TAT polypeptide disclosed herein.

[0708] In particular embodiments, conservative substitutions of interestare shown in Table 6 under the heading of preferred substitutions. Ifsuch substitutions result in a change in biological activity, then moresubstantial changes, denominated exemplary substitutions in Table 6, oras further described below in reference to amino acid classes, areintroduced and the products screened. TABLE 6 Original ExemplaryPreferred Residue Substitutions Substitutions Ala (A) val; leu; ile valArg (R) lys; gln; asn lys Asn (N) gln; his; lys; arg gln Asp (D) glu gluCys (C) ser ser Gln (Q) asn asn Glu (E) asp asp Gly (G) pro; ala ala His(H) asn; gln; lys; arg arg Ile (I) leu; val; met; ala; phe; leunorleucine Leu (L) norleucine; ile; val; ile met; ala; phe Lys (K) arg;gln; asn arg Met (M) leu; phe; ile leu Phe (F) leu; val; ile; ala; tyrleu Pro (P) ala ala Ser (S) thr thr Thr (T) ser ser Trp (W) tyr; phe tyrTyr (Y) trp; phe; thr; ser phe Val (V) ile; leu; met; phe; ala;norleucine leu

[0709] Substantial modifications in function or immunological identityof the anti-TAT antibody or TAT polypeptide are accomplished byselecting substitutions that differ significantly in their effect onmaintaining (a) the structure of the polypeptide backbone in the area ofthe substitution, for example, as a sheet or helical conformation, (b)the charge or hydrophobicity of the molecule at the target site, or (c)the bulk of the side chain. Naturally occurring residues are dividedinto groups based on common side-chain properties:

[0710] (1) hydrophobic: norleucine, met, ala, val, leu, ile;

[0711] (2) neutral hydrophilic: cys, ser, thr;

[0712] (3) acidic: asp, glu;

[0713] (4) basic: asn, gln, his, lys, arg;

[0714] (5) residues that influence chain orientation: gly, pro; and

[0715] (6) aromatic: trp, tyr, phe.

[0716] Non-conservative substitutions will entail exchanging a member ofone of these classes for another class. Such substituted residues alsomay be introduced into the conservative substitution sites or, morepreferably, into the remaining (non-conserved) sites.

[0717] The variations can be made using methods known in the art such asoligonucleotide-mediated (site-directed) mutagenesis, alanine scanning,and PCR mutagenesis. Site-directed mutagenesis [Carter et al., Nucl.Acids Res., 13:4331 (1986); Zoller et al., Nucl. Acids Res., 10:6487(1987)], cassette mutagenesis [Wells et al., Gene, 34:315 (1985)],restriction selection mutagenesis [Wells et al., Philos. Trans. R. Soc.London SerA, 317:415 (1986)] or other known techniques can be performedon the cloned DNA to produce the anti-TAT antibody or TAT polypeptidevariant DNA.

[0718] Scanning amino acid analysis can also be employed to identify oneor more amino acids along a contiguous sequence. Among the preferredscanning amino acids are relatively small, neutral amino acids. Suchamino acids include alanine, glycine, serine, and cysteine. Alanine istypically a preferred scanning amino acid among this group because iteliminates the side-chain beyond the beta-carbon and is less likely toalter the main-chain conformation of the variant [Cunningham and Wells,Science, 244:1081-1085 (1989)]. Alanine is also typically preferredbecause it is the most common amino acid. Further, it is frequentlyfound in both buried and exposed positions [Creighton, The Proteins,(W.H. Freeman & Co., N.Y.); Chothia, J. Mol. Biol., 150:1 (1976)]. Ifalanine substitution does not yield adequate amounts of variant, anisoteric amino acid can be used.

[0719] Any cysteine residue not involved in maintaining the properconformation of the anti-TAT antibody or TAT polypeptide also may besubstituted, generally with serine, to improve the oxidative stabilityof the molecule and prevent aberrant crosslinking. Conversely, cysteinebond(s) may be added to the anti-TAT antibody or TAT polypeptide toimprove its stability (particularly where the antibody is an antibodyfragment such as an Fv fragment).

[0720] A particularly preferred type of substitutional variant involvessubstituting one or more hypervariable region residues of a parentantibody (e.g., a humanized or human antibody). Generally, the resultingvariant(s) selected for further development will have improvedbiological properties relative to the parent antibody from which theyare generated. A convenient way for generating such substitutionalvariants involves affinity maturation using phage display. Briefly,several hypervariable region sites (e.g., 6-7 sites) are mutated togenerate all possible amino substitutions at each site. The antibodyvariants thus generated are displayed in a monovalent fashion fromfilamentous phage particles as fusions to the gene III product of M13packaged within each particle. The phage-displayed variants are thenscreened for their biological activity (e.g., binding affinity) asherein disclosed. In order to identify candidate hypervariable regionsites for modification, alanine scanning mutagenesis can be performed toidentify hypervariable region residues contributing significantly toantigen binding. Alternatively, or additionally, it may be beneficial toanalyze a crystal structure of the antigen-antibody complex to identifycontact points between the antibody and human TAT polypeptide. Suchcontact residues and neighboring residues are candidates forsubstitution according to the techniques elaborated herein. Once suchvariants are generated, the panel of variants is subjected to screeningas described herein and antibodies with superior properties in one ormore relevant assays may be selected for further development.

[0721] Nucleic acid molecules encoding amino acid sequence variants ofthe anti-TAT antibody are prepared by a variety of methods known in theart. These methods include, but are not limited to, isolation from anatural source (in the case of naturally occurring amino acid sequencevariants) or preparation by oligonucleotide-mediated (or site-directed)mutagenesis, PCR mutagenesis, and cassette mutagenesis of an earlierprepared variant or a non-variant version of the anti-TAT antibody.

[0722] H. Modifications of Anti-TAT Antibodies and TAT Polypeptides

[0723] Covalent modifications of anti-TAT antibodies and TATpolypeptides are included within the scope of this invention. One typeof covalent modification includes reacting targeted amino acid residuesof an anti-TAT antibody or TAT polypeptide with an organic derivatizingagent that is capable of reacting with selected side chains or the N— orC-terminal residues of the anti-TAT antibody or TAT polypeptide.Derivatization with bifunctional agents is useful, for instance, forcrosslinking anti-TAT antibody or TAT polypeptide to a water-insolublesupport matrix or surface for use in the method for purifying anti-TATantibodies, and vice-versa. Commonly used crosslinking agents include,e.g., 1,1-bis(diazoacetyl)-2-phenylethane, glutaraldehyde,N-hydroxysuccinimide esters, for example, esters with 4-azidosalicylicacid, homobifunctional imidoesters, including disuccinimidyl esters suchas 3,3′-dithiobis(succinimidylpropionate), bifunctional maleimides suchas bis-N-maleimido-1,8-octane and agents such asmethyl-3-[(p-azidophenyl)dithio]propioimidate.

[0724] Other modifications include deamidation of glutaminyl andasparaginyl residues to the corresponding glutamyl and aspartylresidues, respectively, hydroxylation of proline and lysine,phosphorylation of hydroxyl groups of seryl or threonyl residues,methylation of the α-amino groups of lysine, arginine, and histidineside chains [T. E. Creighton, Proteins: Structure and MolecularProperties, W.H. Freeman & Co., San Francisco, pp. 79-86 (1983)],acetylation of the N-terminal amine, and amidation of any C-terminalcarboxyl group.

[0725] Another type of covalent modification of the anti-TAT antibody orTAT polypeptide included within the scope of this invention comprisesaltering the native glycosylation pattern of the antibody orpolypeptide. “Altering the native glycosylation pattern” is intended forpurposes herein to mean deleting one or more carbohydrate moieties foundin native sequence anti-TAT antibody or TAT polypeptide (either byremoving the underlying glycosylation site or by deleting theglycosylation by chemical and/or enzymatic means), and/or adding one ormore glycosylation sites that are not present in the native sequenceanti-TAT antibody or TAT polypeptide. In addition, the phrase includesqualitative changes in the glycosylation of the native proteins,involving a change in the nature and proportions of the variouscarbohydrate moieties present.

[0726] Glycosylation of antibodies and other polypeptides is typicallyeither N-linked or O-linked. N-linked refers to the attachment of thecarbohydrate moiety to the side chain of an asparagine residue. Thetripeptide sequences asparagine-X-serine and asparagine-X-threonine,where X is any amino acid except proline, are the recognition sequencesfor enzymatic attachment of the carbohydrate moiety to the asparagineside chain. Thus, the presence of either of these tripeptide sequencesin a polypeptide creates a potential glycosylation site. O-linkedglycosylation refers to the attachment of one of the sugarsN-aceylgalactosamine, galactose, or xylose to a hydroxyamino acid, mostcommonly serine or threonine, although 5-hydroxyproline or5-hydroxylysine may also be used.

[0727] Addition of glycosylation sites to the anti-TAT antibody or TATpolypeptide is conveniently accomplished by altering the amino acidsequence such that it contains one or more of the above-describedtripeptide sequences (for N-linked glycosylation sites). The alterationmay also be made by the addition of, or substitution by, one or moreserine or threonine residues to the sequence of the original anti-TATantibody or TAT polypeptide (for O-linked glycosylation sites). Theanti-TAT antibody or TAT polypeptide amino acid sequence may optionallybe altered through changes at the DNA level, particularly by mutatingthe DNA encoding the anti-TAT antibody or TAT polypeptide at preselectedbases such that codons are generated that will translate into thedesired amino acids.

[0728] Another means of increasing the number of carbohydrate moietieson the anti-TAT antibody or TAT polypeptide is by chemical or enzymaticcoupling of glycosides to the polypeptide. Such methods are described inthe art, e.g., in WO 87/05330 published 11 Sep. 1987, and in Aplin andWriston, CRC Crit. Rev. Biochem., pp. 259-306 (1981).

[0729] Removal of carbohydrate moieties present on the anti-TAT antibodyor TAT polypeptide may be accomplished chemically or enzymatically or bymutational substitution of codons encoding for amino acid residues thatserve as targets for glycosylation. Chemical deglycosylation techniquesare known in the art and described, for instance, by Hakimuddin, et al.,Arch. Biochem. Biophys., 259:52 (1987) and by Edge et al., Anal.Biochem., 118:131 (1981). Enzymatic cleavage of carbohydrate moieties onpolypeptides can be achieved by the use of a variety of endo- andexo-glycosidases as described by Thotakura et al., Meth. Enzymol.,138:350 (1987).

[0730] Another type of covalent modification of anti-TAT antibody or TATpolypeptide comprises linking the antibody or polypeptide to one of avariety of nonproteinaceous polymers, e.g., polyethylene glycol (PEG),polypropylene glycol, or polyoxyalkylenes, in the manner set forth inU.S. Pat. Nos. 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192 or4,179,337. The antibody or polypeptide also may be entrapped inmicrocapsules prepared, for example, by coacervation techniques or byinterfacial polymerization (for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively), in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules), or in macroemulsions. Such techniques are disclosediRemington's Pharmaceutical Sciences, 16th edition, Oslo, A., Ed.,(1980).

[0731] The anti-TAT antibody or TAT polypeptide of the present inventionmay also be modified in a way to form chimeric molecules comprising ananti-TAT antibody or TAT polypeptide fused to another, heterologouspolypeptide or amino acid sequence.

[0732] In one embodiment, such a chimeric molecule comprises a fusion ofthe anti-TAT antibody or TAT polypeptide with a tag polypeptide whichprovides an epitope to which an anti-tag antibody can selectively bind.The epitope tag is generally placed at the amino- or carboxyl- terminusof the anti-TAT antibody or TAT polypeptide. The presence of suchepitope-tagged forms of the anti-TAT antibody or TAT polypeptide can bedetected using an antibody against the tag polypeptide. Also, provisionof the epitope tag enables the anti-TAT antibody or TAT polypeptide tobe readily purified by affinity purification using an anti-tag antibodyor another type of affinity matrix that binds to the epitope tag.Various tag polypeptides and their respective antibodies are well knownin the art. Examples include poly-histidine (poly-his) orpoly-histidine-glycine (poly-his-gly) tags; the flu HA tag polypeptideand its antibody 12CA5 [Field et al., Mol. Cell. Biol., 8:2159-2165(1988)]; the c-myc tag and the 8F9,3C7,6E10, G4, B7 and 9E10 antibodiesthereto [Evan et al., Molecular and Cellular Biology, 5:3610-3616(1985)]; and the Herpes Simplex virus glycoprotein D (gD) tag and itsantibody [Paborsky et al., Protein Engineering, 3(6):547-553 (1990)].Other tag polypeptides include the Flag-peptide [Hopp et aBioTechnology,6:1204-1210 (1988)]; the KT3 epitope peptide [Martin et al., Science,255:192-194 (1992)]; an α-tubuiln epitope peptide [Skinner et al., J.Biol. Chem., 266:15163-15166 (1991)]; and the T7 gene 10 protein peptidetag [Lutz-Freyermuth et al., Proc. Natl. Acad. Sci. USA, 87:6393-6397(1990)].

[0733] In an alternative embodiment, the chimeric molecule may comprisea fusion of the anti-TAT antibody or TAT polypeptide with animmunoglobulin or a particular region of an immunoglobulin. For abivalent form of the chimeric molecule (also referred to as an“immunoadhesin”), such a fusion could be to the Fc region of an IgGmolecule. The Ig fusions preferably include the substitution of asoluble (transmembrane domain deleted or inactivated) form of ananti-TAT antibody or TAT polypeptide in place of at least one variableregion within an Ig molecule. In a particularly preferred embodiment,the immunoglobulin fusion includes the hinge, CH₂ and CH₃, or the hinge,CH₁, CH₂ and CH₃ regions of an IgG1 molecule. For the production ofimmunoglobulin fusions see also U.S. Pat. No. 5,428,130 issued Jun. 27,1995.

[0734] I. Preparation of Anti-TAT Antibodies and TAT Polypeptides

[0735] The description below relates primarily to production of anti-TATantibodies and TAT polypeptides by culturing cells transformed ortransfected with a vector containing anti-TAT antibody- and TATpolypeptide-encoding nucleic acid. It is, of course, contemplated thatalternative methods, which are well known in the art, may be employed toprepare anti-TAT antibodies and TAT polypeptides. For instance, theappropriate amino acid sequence, or portions thereof, may be produced bydirect peptide synthesis using solid-phase techniques [see, e.g.,Stewart et al., Solid-Phase Peptide Synthesis, W.H. Freeman Co., SanFrancisco, Calif. (1969); Merrifield, J. Am. Chem. Soc., 85:2149-2154(1963)]. In vitro protein synthesis may be performed using manualtechniques or by automation. Automated synthesis may be accomplished,for instance, using an Applied Biosystems Peptide Synthesizer (FosterCity, Calif.) using manufacturer's instructions. Various portions of theanti-TAT antibody or TAT polypeptide may be chemically synthesizedseparately and combined using chemical or enzymatic methods to producethe desired anti-TAT antibody or TAT polypeptide.

[0736] 1. Isolation of DNA Encoding Anti-TAT Antibody or TAT Polypeptide

[0737] DNA encoding anti-TAT antibody or TAT polypeptide may be obtainedfrom a cDNA library prepared from tissue believed to possess theanti-TAT antibody or TAT polypeptide mRNA and to express it at adetectable level. Accordingly, human anti-TAT antibody or TATpolypeptide DNA can be conveniently obtained from a cDNA libraryprepared from human tissue. The anti-TAT antibody- or TATpolypeptide-encoding gene may also be obtained from a genomic library orby known synthetic procedures (e.g., automated nucleic acid synthesis).

[0738] Libraries can be screened with probes (such as oligonucleotidesof at least about 20-80 bases) designed to identify the gene of interestor the protein encoded by it. Screening the cDNA or genomic library withthe selected probe may be conducted using standard procedures, such asdescribed in Sambrook et al., Molecular Cloning: A Laboratory Manual(New York: Cold Spring Harbor Laboratory Press, 1989). An alternativemeans to isolate the gene encoding anti-TAT antibody or TAT polypeptideis to use PCR methodology [Sambrook et al., supra; Dieffenbach et al.,PCR Primer: A Laboratory Manual (Cold Spring Harbor Laboratory Press,1995)].

[0739] Techniques for screening a cDNA library are well known in theart. The oligonucleotide sequences selected as probes should be ofsufficient length and sufficiently unambiguous that false positives areminimized. The oligonucleotide is preferably labeled such that it can bedetected upon hybridization to DNA in the library being screened.Methods of labeling are well known in the art, and include the use ofradiolabels like P-labeled ATP, biotinylation or enzyme labeling.Hybridization conditions, including moderate stringency and highstringency, are provided in Sambrook et al., supra.

[0740] Sequences identified in such library screening methods can becompared and aligned to other known sequences deposited and available inpublic databases such as GenBank or other private sequence databases.Sequence identity (at either the amino acid or nucleotide level) withindefined regions of the molecule or across the full-length sequence canbe determined using methods known in the art and as described herein.

[0741] Nucleic acid having protein coding sequence may be obtained byscreening selected cDNA or genomic libraries using the deduced aminoacid sequence disclosed herein for the first time, and, if necessary,using conventional primer extension procedures as described in Sambrooket al., supra, to detect precursors and processing intermediates of mRNAthat may not have been reverse-transcribed into cDNA.

[0742] 2. Selection and Transformation of Host Cells

[0743] Host cells are transfected or transformed with expression orcloning vectors described herein for anti-TAT antibody or TATpolypeptide production and cultured in conventional nutrient mediamodified as appropriate for inducing promoters, selecting transformants,or amplifying the genes encoding the desired sequences. The cultureconditions, such as media, temperature, pH and the like, can be selectedby the skilled artisan without undue experimentation. In general,principles, protocols, and practical techniques for maximizing theproductivity of cell cultures can be found in Mammalian CellBiotechnology: a Practical Approach M. Butler, ed. (IRL Press, 1991) andSambrook et al., supra.

[0744] Methods of eukaryotic cell transfection and prokaryotic celltransformation are known to the ordinarily skilled artisan, for example,CaCl₂, CaPO₄, liposome-mediated and electroporation. Depending on thehost cell used, transformation is performed using standard techniquesappropriate to such cells. The calcium treatment employing calciumchloride, as described in Sambrook et al., supra, or electroporation isgenerally used for prokaryotes. Infection with Agrobacterium tumefaciensis used for transformation of certain plant cells, as described by Shawet al., Gene, 23:315 (1983) and WO 89/05859 published 29 Jun. 1989. Formammalian cells without such cell walls, the calcium phosphateprecipitation method of Graham and van der Eb, Virology, 52:456-457(1978) can be employed. General aspects of mammalian cell host systemtransfections have been described in U.S. Pat. No. 4,399,216.Transformations into yeast are typically carried out according to themethod of Van Solingen et al., J. Bact., 130:946 (1977) and Hsiao etal., Proc. Natl. Acad. Sci. (USA), 76:3829 (1979). However, othermethods for introducing DNA into cells, such as by nuclearmicroinjection, electroporation, bacterial protoplast fusion with intactcells, or polycations, e.g., polybrene, polyornithine, may also be used.For various techniques for transforming mammalian cells, see Keown etal., Methods in Enzymology, 185:527-537 (1990) and Mansour et al.,Nature, 336:348-352 (1988).

[0745] Suitable host cells for cloning or expressing the DNA in thevectors herein include prokaryote, yeast, or higher eukaryote cells.Suitable prokaryotes include but are not limited to eubacteria, such asGram-negative or Gram-positive organisms, for example,Enterobacteriaceae such as E. coli. Various E. coli strains are publiclyavailable, such as E. coli K12 strain MM294 (ATCC 31,446); E. coli X1776(ATCC31,537); E. coli strain W3110 (ATCC 27,325) and K5 772 (ATCC53,635). Other suitable prokaryotic host cells includeEnterobacteriaceae such as Escherichia, e.g., E. coli, Enterobacter,Erwinia, Klebsiella, Proteus, Salinotiella, e.g., Salinonellatyphimurium, Serratia, e.g., Serratia marcescans, and Shigella, as wellas Bacilli such as B. subtilis and B. licheniformis (e.g., B.licheniformis 41P disclosed in DD 266,710 published 12 Apr. 1989),Pseudomonas such as P. aeruginosa, and Streptomyces. These examples areillustrative rather than limiting. Strain W3110 is one particularlypreferred host or parent host because it is a common host strain forrecombinant DNA product fermentations. Preferably, the host cellsecretes minimal amounts of proteolytic enzymes. For example, strainW3110 may be modified to effect a genetic mutation in the genes encodingproteins endogenous to the host, with examples of such hosts includingE. coli W3110 strain 1A2, which has the complete genotype tonA ; E. coliW3110 strain 9E4, which has the complete genotype tonA ptr3, E. coliW3110 strain 27C7 (ATCC 55,244) which has the complete genotype tonAptr3 phoA E15 (argF-lac)169 degP ompT kan E. coli W3110 strain 37D6,which has the complete genotype tonA ptr3 phoA E15 (argF-lac)169 degPompT rbs7 ilvG kan E. coli W3110 strain 40B4, which is strain 37D6 witha non-kanamycin resistant degP deletion mutation; and an E. coli strainhaving mutant periplasmic protease disclosed in U.S. Pat. No. 4,946,783issued 7 Aug. 1990. Alternatively, in vitro methods of cloning, e.g.,PCR or other nucleic acid polymerase reactions, are suitable.

[0746] Full length antibody, antibody fragments, and antibody fusionproteins can be produced in bacteria, in particular when glycosylationand Fc effector function are not needed, such as when the therapeuticantibody is conjugated to a cytotoxic agent (e.g., a toxin) and theimmunoconjugate by itself shows effectiveness in tumor cell destruction.Full length antibodies have greater half life in circulation. Productionin E. coli is faster and more cost efficient. For expression of antibodyfragments and polypeptides in bacteria, see, e.g., U.S. Pat. No.5,648,237 (Carter et. al.), U.S. Pat. No. 5,789,199 (Joly et al.), andU.S. Pat. No. 5,840,523 (Simmons et al.) which describes translationinitiation regio (TIR) and signal sequences for optimizing expressionand secretion, these patents incorporated herein by reference. Afterexpression, the antibody is isolated from the E. coli cell paste in asoluble fraction and can be purified through, e.g., a protein A or Gcolumn depending on the isotype. Final purification can be carried outsimilar to the process for purifying antibody expressed e.g,, in CHOcells.

[0747] In addition to prokaryotes, eukaryotic microbes such asfilamentous fungi or yeast are suitable cloning or expression hosts foranti-TAT antibody- or TAT polypeptide-encoding vectors. Saccharomycescerevisiae is a commonly used lower eukaryotic host microorganism.Others include Schizosaccharomyces pombe (Beach and Nurse, Nature, 290:140 [1981];EP 139,383 published 2 May 1985); Kluyveromyces hosts (U.S.Pat. No. 4,943,529; Fleer et al., Bio/Technology, 9:968-975 (1991)) suchas, e.g., K. lactis (MW98-8C, CBS683, CBS4574; Louvencourt et al., J.Bacteriol., 154(2):737-742 [1983]), K. fragilis (ATCC 12,424), K.bulgaricus (ATCC 16,045), K. wickeramii (ATCC 24,178), K. waltii (ATCC56,500), K. drosophilarum (ATCC 36,906; Van den Berg et al.,Bio/Technology, 8:135 (1990)), K. thermotolerans, and K. marxianus;yarrowia (EP 402,226); Pichia pastoris (EP 183,070; Sreekrishna et al.,J. Basic Microbiol., 28:265-278 [1988]); Candida; Trichoderma reesia (EP244,234); Neurospora crassa (Case et al., Proc. Natl. Acad. Sci. USA,76:5259-5263 [1979]); Schwanniomyces such as Schwanniomyces occidentalis(EP 394,538 published 31 Oct. 1990); and filamentous fungi such as,e.g., Neurospora, Penicillium, Tolypocladium (WO 91/00357 published 10Jan. 1991), and Aspergillus hosts such as A. nidulans (Ballance et al.,Biochem. Biophys. Res. Commun., 112:284-289 [1983]; Tilburn et al.,Gene, 26:205-221 [1983]; Yelton et al., Proc. Natl. Acad. Sci. USA, 81:1470-1474 [1984]) and A. niger (Kelly and Hynes, EMBO J., 4:475-479[1985]). Methylotropic yeasts are suitable herein and include, but arenot limited to, yeast capable of growth on methanol selected from thegenera consisting of Hansenula, Candida, Kloeckera, Pichia,Saccharomyces, Torulopsis, and Rhodotorula. A list of specific speciesthat are exemplary of this class of yeasts may be found in C. Anthony,The Biochemistry of Methylotrophs, 269 (1982).

[0748] Suitable host cells for the expression of glycosylated anti-TATantibody or TAT polypeptide are derived from multicellular organisms.Examples of invertebrate cells include insect cells such as DrosophilaS2 and Spodoptera Sf9, as well as plant cells, such as cell cultures ofcotton, corn, potato, soybean, petunia, tomato, and tobacco. Numerousbaculoviral strains and variants and corresponding permissive insecthost cells from hosts such as Spodoptera frugiperda (caterpillar), Aedesaegypti (mosquito), Aedes albopictus (mosquito), Drosophila melanogaster(fruitfly), and Bombyx mori have been identified. A variety of viralstrains for transfection are publicly available, e.g., the L-1 variantof Autographa californica NPV and the Bm-5 strain of Bombyx mori NPV,and such viruses may be used as the virus herein according to thepresent invention, particularly for transfection of Spodopterafrugiperda cells.

[0749] However, interest has been greatest in vertebrate cells, andpropagation of vertebrate cells in culture (tissue culture) has become aroutine procedure. Examples of useful mammalian host cell lines aremonkey kidney CV1 line transformed by SV40 (COS-7, ATCC CRL 1651); humanembryonic kidney line (293 or 293 cells subcloned for growth insuspension culture, Graham et al., J. Gen Virol. 36:59 (1977)); babyhamster kidney cells (BHK, ATCC CCL 10); Chinese hamster ovarycells/-DHFR (CHO, Urlaub et al., Proc. Natl. Acad. Sci. USA 77:4216(1980)); mouse sertoli cells (TM4, Mather, Biol. Reprod. 23:243-251(1980)); monkey kidney cells (CV1 ATCC CCL 70); African green monkeykidney cells (VERO-76, ATCC CRL-1587); human cervical carcinoma cells(HELA, ATCC CCL 2); canine kidney cells (MDCK, ATCC CCL 34); buffalo ratliver cells (BRL 3A, ATCC CRL 1442); human lung cells (W138, ATCC CCL75); human liver cells (Hep G2, HB 8065); mouse mammary tumor (MMT060562, ATCC CCL51); TRI cells (Mather et al., Annals N.Y. Acad. Sci.383:44-68 (1982)); MRC 5 cells; FS4 cells; and a human hepatoma line(Hep G2).

[0750] Host cells are transformed with the above-described expression orcloning vectors for anti-TAT antibody or TAT polypeptide production andcultured in conventional nutrient media modified as appropriate forinducing promoters, selecting transformants, or amplifying the genesencoding the desired sequences.

[0751] 3. Selection and Use of a Replicable Vector

[0752] The nucleic acid (e.g., cDNA or genomic DNA) encoding anti-TATantibody or TAT polypeptide may be inserted into a replicable vector forcloning (amplification of the DNA) or for expression. Various vectorsare publicly available. The vector may, for example, be in the form of aplasmid, cosmid, viral particle, or phage. The appropriate nucleic acidsequence may be inserted into the vector by a variety of procedures. Ingeneral, DNA is inserted into an appropriate restriction endonucleasesite(s) using techniques known in the art. Vector components generallyinclude, but are not limited to, one or more of a signal sequence, anorigin of replication, one or more marker genes, an enhancer element, apromoter, and a transcription termination sequence. Construction ofsuitable vectors containing one or more of these components employsstandard ligation techniques which are known to the skilled artisan.

[0753] The TAT may be produced recombinantly not only directly, but alsoas a fusion polypeptide with a heterologous polypeptide, which may be asignal sequence or other polypeptide having a specific cleavage site atthe N-terminus of the mature protein or polypeptide. In general, thesignal sequence may be a component of the vector, or it may be a part ofthe anti-TAT antibody- or TAT polypeptide-encoding DNA that is insertedinto the vector. The signal sequence may be a prokaryotic signalsequence selected, for example, from the group of the alkalinephosphatase, penicillinase, lpp, or heat-stable enterotoxin II leaders.For yeast secretion the signal sequence may be, e.g., the yeastinvertase leader, alpha factor leader (including Saccharomyces andKluyveromyces α-factor leaders, the latter described in U.S. Pat. No.5,010,182), or acid phosphatase leader, the C. albicans glucoamylaseleader (EP 362,179 published 4 Apr. 1990), or the signal described in WO90/13646 published 15 Nov. 1990. In mammalian cell expression, mammaliansignal sequences may be used to direct secretion of the protein, such assignal sequences from secreted polypeptides of the same or relatedspecies, as well as viral secretory leaders.

[0754] Both expression and cloning vectors contain a nucleic acidsequence that enables the vector to replicate in one or more selectedhost cells. Such sequences are well known for a variety of bacteria,yeast, and viruses. The origin of replication from the plasmid pBR322 issuitable for most Gram-negative bacteria, the 2μplasmid origin issuitable for yeast, and various viral origins (SV40, polyoma,adenovirus, VSV or BPV) are useful for cloning vectors in mammaliancells.

[0755] Expression and cloning vectors will typically contain a selectiongene, also termed a selectable marker. Typical selection genes encodeproteins that (a) confer resistance to antibiotics or other toxins,e.g., ampicillin, neomycin, methotrexate, or tetracycline, (b)complement auxotrophic deficiencies, or (c) supply critical nutrientsnot available from complex media, e.g., the gene encoding D-alanineracemase for Bacilli.

[0756] An example of suitable selectable markers for mammalian cells arethose that enable the identification of cells competent to take up theanti-TAT antibody- or TAT polypeptide-encoding nucleic acid, such asDHFR or thymidine kinase. An appropriate host cell when wild-type DHFRis employed is the CHO cell line deficient in DHFR activity, preparedand propagated as described by Urlaub et al., Proc. Natl. Acad. Sci.USA, 77:4216 (1980). A suitable selection gene for use in yeast istherp1 gene present in the yeast plasmid YRp7 [Stinchcomb et al.,Nature, 282:39 (1979); Kingsman et al., Gene, 7:141 (1979); Tschemper etal., Gene, 10:157 (1980)]. The trp1 gene provides a selection marker fora mutant strain of yeast lacking the ability to grow in tryptophan, forexample, ATCC No. 44076 or PEP4-1 [Jones, Genetics, 85:12 (1977)].

[0757] Expression and cloning vectors usually contain a promoteroperably linked to the anti-TAT antibody—or TAT polypeptide-encodingnucleic acid sequence to direct mRNA synthesis. Promoters recognized bya variety of potential host cells are well known. Promoters suitable foruse with prokaryotic hosts include theβ-lactamase and lactose promotersystems [Chang et al., Nature, 275:615 (1978); Goeddel et al., Nature,281:544 (1979)], alkaline phosphatase, a tryptophan (trp) promotersystem [Goeddel, Nucleic Acids Res., 8:4057 (1980); EP 36,776], andhybrid promoters such as the tac promoter [deBoer et al., Proc. Natl.Acad. Sci. USA, 80:21-25 (1983)]. Promoters for use in bacterial systemsalso will contain a Shine-Dalgarno (S.D.) sequence operably linked tothe DNA encoding anti-TAT antibody or TAT polypeptide.

[0758] Examples of suitable promoting sequences for use with yeast hostsinclude the promoters for 3-phosphoglycerate kinase [Hitzeman et al., J.Biol. Chem., 255:2073 (1980)] or other glycolytic enzymes [Hess et al.,J. Adv. Enzyme Reg.,7:149 (1968); Holland, Biochemistry, 17:4900(1978)], such as enolase, glyceraldehyde-3-phosphate dehydrogenase,hexokinase, pyruvate decarboxylase, phosphofructokinase,glucose-6-phosphate isomerase, 3-phosphoglycerate mutase, pyruvatekinase, triosephosphate isomerase, phosphoglucose isomerase, andglucokinase.

[0759] Other yeast promoters, which are inducible promoters having theadditional advantage of transcription controlled by growth conditions,are the promoter regions for alcohol dehydrogenase 2, isocytochrome C,acid phosphatase, degradative enzymes associated with nitrogenmetabolism, metallothionein, glyceraldehyde-3-phosphate dehydrogenase,and enzymes responsible for maltose and galactose utilization. Suitablevectors and promoters for use in yeast expression are further describedin EP 73,657.

[0760] Anti-TAT antibody or TAT polypeptide transcription from vectorsin mammalian host cells is controlled, for example, by promotersobtained from the genomes of viruses such as polyoma virus, fowlpoxvirus (UK 2,211,504 published 5 Jul. 1989), adenovirus (such asAdenovirus 2), bovine papilloma virus, avian sarcoma virus,cytomegalovirus, a retrovirus, hepatitis-B virus and Simian Virus 40(SV40), from heterologous mammalian promoters, e.g., the actin promoteror an immunoglobulin promoter, and from heat-shock promoters, providedsuch promoters are compatible with the host cell systems.

[0761] Transcription of a DNA encoding the anti-TAT antibody or TATpolypeptide by higher eukaryotes may be increased by inserting anenhancer sequence into the vector. Enhancers are cis-acting elements ofDNA, usually about from 10 to 300 bp, that act on a promoter to increaseits transcription. Many enhancer sequences are now known from mammaliangenes (globin, elastase, albumin, α-fetoprotein, and insulin).Typically, however, one will use an enhancer from a eukaryotic cellvirus. Examples include the SV40 enhancer on the late side of thereplication origin (bp 100-270), the cytomegalovirus early promoterenhancer, the polyoma enhancer on the late side of the replicationorigin, and adenovirus enhancers. The enhancer may be spliced into thevector at a position 5′ or 3′ to the anti-TAT antibody or TATpolypeptide coding sequence, but is preferably located at a site 5′ fromthe promoter.

[0762] Expression vectors used in eukaryotic host cells (yeast, fungi,insect, plant, animal, human, or nucleated cells from othermulticellular organisms) will also contain sequences necessary for thetermination of transcription and for stabilizing the mRNA. Suchsequences are commonly available from the 5′ and, occasionally 3′,untranslated regions of eukaryotic or viral DNAs or cDNAs. These regionscontain nucleotide segments transcribed as polyadenylated fragments inthe untranslated portion of the mRNA encoding anti-TAT antibody or TATpolypeptide.

[0763] Still other methods, vectors, and host cells suitable foradaptation to the synthesis of anti-TAT antibody or TAT polypeptide inrecombinant vertebrate cell culture are described in Gething et al.,Nature, 293:620-625 (1981); Mantei et al., Nature, 281:40-46 (1979); EP117,060; and EP 117,058.

[0764] 4. Culturing the Host Cells

[0765] The host cells used to produce the anti-TAT antibody or TATpolypeptide of this invention may be cultured in a variety of media.Commercially available media such as Ham's F10 (Sigma), MinimalEssential Medium ((MEM), (Sigma), RPMI-1640 (Sigma), and Dulbecco'sModified Eagle's Medium ((DMEM), Sigma) are suitable for culturing thehost cells. In addition, any of the media described in Ham et al., Meth.Enz. 58:44 (1979), Barnes et al., Anal. Biochem.102:255 (1980), U.S.Pat. Nos. 4,767,704; 4,657,866; 4,927,762; 4,560,655; or 5,122,469; WO90/03430; WO 87/00195; or U.S. Pat. Re. 30,985 may be used as culturemedia for the host cells. Any of these media may be supplemented asnecessary with hormones and/or other growth factors (such as insulin,transferrin, or epidermal growth factor), salts (such as sodiumchloride, calcium, magnesium, and phosphate), buffers (such as HEPES),nucleotides (such as adenosine and thymidine), antibiotics (such asGENTAMYCIN™ drug), trace elements (defined as inorganic compoundsusually present at final concentrations in the micromolar range), andglucose or an equivalent energy source. Any other necessary supplementsmay also be included at appropriate concentrations that would be knownto those skilled in the art. The culture conditions, such astemperature, pH, and the like, are those previously used with the hostcell selected for expression, and will be apparent to the ordinarilyskilled artisan.

[0766] 5. Detecting Gene Amplification/Expression

[0767] Gene amplification and/or expression may be measured in a sampledirectly, for example, by conventional Southern blotting, Northernblotting to quantitate the transcription of mRNA [Thomas, Proc. Natl.Acad. Sci. USA, 77:5201-5205 (1980)], dot blotting (DNA analysis), or insitu hybridization, using an appropriately labeled probe, based on thesequences provided herein. Alternatively, antibodies may be employedthat can recognize specific duplexes, including DNA duplexes, RNAduplexes, and DNA-RNA hybrid duplexes or DNA-protein duplexes. Theantibodies in turn may be labeled and the assay may be carried out wherethe duplex is bound to a surface, so that upon the formation of duplexon the surface, the presence of antibody bound to the duplex can bedetected.

[0768] Gene expression, alternatively, may be measured by immunologicalmethods, such as immunohistochemical staining of cells or tissuesections and assay of cell culture or body fluids, to quantitatedirectly the expression of gene product. Antibodies useful forimmunohistochemical staining and/or assay of sample fluids may be eithermonoclonal or polyclonal, and may be prepared in any mammal.Conveniently, the antibodies may be prepared against a native sequenceTAT polypeptide or against a synthetic peptide based on the DNAsequences provided herein or against exogenous sequence fused to TAT DNAand encoding a specific antibody epitope.

[0769] 6. Purification of Anti-TAT Antibody and TAT Polypeptide

[0770] Forms of anti-TAT antibody and TAT polypeptide may be recoveredfrom culture medium or from host cell lysates. If membrane-bound, it canbe released from the membrane using a suitable detergent solution (e.g.Triton-X 100) or by enzymatic cleavage. Cells employed in expression ofanti-TAT antibody and TAT polypeptide can be disrupted by variousphysical or chemical means, such as freeze-thaw cycling, sonication,mechanical disruption, or cell lysing agents.

[0771] It may be desired to purify anti-TAT antibody and TAT polypeptidefrom recombinant cell proteins or polypeptides. The following proceduresare exemplary of suitable purification procedures: by fractionation onan ion-exchange column; ethanol precipitation; reverse phase HPLC;chromatography on silica or on a cation-exchange resin such as DEAE;chromatofocusing; SDS-PAGE; ammonium sulfate precipitation; gelfiltration using, for example, Sephadex G-75; protein A Sepharosecolumns to remove contaminants such as IgG; and metal chelating columnsto bind epitope-tagged forms of the anti-TAT antibody and TATpolypeptide. Various methods of protein purification may be employed andsuch methods are known in the art and described for example inDeutscher, Methods in Enzymology, 182 (1990); Scopes, ProteinPurification: Principles and Practice, Springer-Verlag, New York (1982).The purification step(s) selected will depend, for example, on thenature of the production process used and the particular anti-TATantibody or TAT polypeptide produced.

[0772] When using recombinant techniques, the antibody can be producedintracellularly, in the periplasmic space, or directly secreted into themedium. If the antibody is produced intracellularly, as a first step,the particulate debris, either host cells or lysed fragments, areremoved, for example, by centrifugation or ultrafiltration. Carter etal., Bio/Technology 10:163-167 (1992) describe a procedure for isolatingantibodies which are secreted to the periplasmic space of E. coli.Briefly, cell paste is thawed in the presence of sodium acetate (pH3.5), EDTA, and phenylmethylsulfonylfluoride (PMSF) over about 30 min.Cell debris can be removed by centrifugation. Where the antibody issecreted into the medium, supernatants from such expression systems aregenerally first concentrated using a commercially available proteinconcentration filter, for example, an Amicon or Millipore Pelliconultrafiltration unit. A protease inhibitor such as PMSF may be includedin any of the foregoing steps to inhibit proteolysis and antibiotics maybe included to prevent the growth of adventitious contaminants.

[0773] The antibody composition prepared from the cells can be purifiedusing, for example, hydroxylapatite chromatography, gel electrophoresis,dialysis, and affinity chromatography, with affinity chromatographybeing the preferred purification technique. The suitability of protein Aas an affinity ligand depends on the species and isotype of anyimmunoglobulin Fc domain that is present in the antibody. Protein A canbe used to purify antibodies that are based on human γ1, γ2 or γ4 heavychains (Lindmark et al., J. Immunol. Meth. 62:1-13 (1983)). Protein G isrecommended for all mouse isotypes and for humanγ3 (Guss et al., EMBO J.5:15671575 (1986)). The matrix to which the affinity ligand is attachedis most often agarose, but other matrices are available. Mechanicallystable matrices such as controlled pore glass orpoly(styrenedivinyl)benzene allow for faster flow rates and shorterprocessing times than can be achieved with agarose. Where the antibodycomprises a C_(H)3 domain, the Bakerbond ABX™resin (J. T. Baker,Phillipsburg, N.J.) is useful for purification. Other techniques forprotein purification such as fractionation on an ion-exchange column,ethanol precipitation, Reverse Phase HPLC, chromatography on silica,chromatography on heparin SEPHAROSE™ chromatography on an anion orcation exchange resin (such as a polyaspartic acid column),chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation are alsoavailable depending on the antibody to be recovered.

[0774] Following any preliminary purification step(s), the mixturecomprising the antibody of interest and contaminants may be subjected tolow pH hydrophobic interaction chromatography using an elution buffer ata pH between about 2.5-4.5, preferably performed at low saltconcentrations (e.g., from about 0-0.25M salt).

[0775] J. Pharmaceutical Formulations

[0776] Therapeutic formulations of the anti-TAT antibodies, TAT bindingoligopeptides, TAT binding organic molecules and/or TAT polypeptidesused in accordance with the present invention are prepared for storageby mixing the antibody, polypeptide, oligopeptide or organic moleculehaving the desired degree of purity with optional pharmaceuticallyacceptable carriers, excipients or stabilizersR(emington'sPharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the formof lyophilized formulations or aqueous solutions. Acceptable carriers,excipients, or stabilizers are nontoxic to recipients at the dosages andconcentrations employed, and include buffers such as acetate, Tris,phosphate, citrate, and other organic acids; antioxidants includingascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides, and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; tonicifiers such as trehaloseand sodium chloride; sugars such as sucrose, mannitol, trehalose orsorbitol; surfactant such as polysorbate; salt-forming counter-ions suchas sodium; metal complexes (e.g., Zn-protein complexes); and/ornon-ionic surfactants such as TWEEN®, PLURONICS® or polyethylene glycol(PEG). The antibody preferably comprises the antibody at a concentrationof between 5-200 mg/ml, preferably between 10-100 mg/ml.

[0777] The formulations herein may also contain more than one activecompound as necessary for the particular indication being treated,preferably those with complementary activities that do not adverselyaffect each other. For example, in addition to an anti-TAT antibody, TATbinding oligopeptide, or TAT binding organic molecule, it may bedesirable to include in the one formulation, an additional antibody,e.g., a second anti-TAT antibody which binds a different epitope on theTAT polypeptide, or an antibody to some other target such as a growthfactor that affects the growth of the particular cancer. Alternatively,or additionally, the composition may further comprise a chemotherapeuticagent, cytotoxic agent, cytokine, growth inhibitory agent, anti-hormonalagent, and/or cardioprotectant. Such molecules are suitably present incombination in amounts that are effective for the purpose intended.

[0778] The active ingredients may also be entrapped in microcapsulesprepared, for example, by coacervation techniques or by interfacialpolymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington's Pharmaceutical Sciences, 16th edition, Osol, A. Ed. (1980).

[0779] Sustained-release preparations may be prepared. Suitable examplesof sustained-release preparations include semi-permeable matrices ofsolid hydrophobic polymers containing the antibody, which matrices arein the form of shaped articles, e.g., films, or microcapsules. Examplesof sustained-release matrices include polyesters, hydrogels (forexample, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)),polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acidand γ ethyl-L-glutamate, non-degradable ethylene-vinyl acetate,degradable lactic acid-glycolic acid copolymers such as the LUPRONDEPOT® (injectable microspheres composed of lactic acid-glycolic acidcopolymer and leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid.

[0780] The formulations to be used for in vivo administration must besterile. This is readily accomplished by filtration through sterilefiltration membranes.

[0781] K. Diagnosis and Treatment with Anti-TAT Antibodies, TAT BindingOligoneptides and TAT Binding Organic Molecules

[0782] To determine TAT expression in the cancer, various diagnosticassays are available. In one embodiment, TAT polypeptide overexpressionmay be analyzed by immunohistochemistry (IHC). Parrafin embedded tissuesections from a tumor biopsy may be subjected to the IHC assay andaccorded a TAT protein staining intensity criteria as follows:

[0783] Score 0 —no staining is observed or membrane staining is observedin less than 10% of tumor cells.

[0784] Score 1+—a faint/barely perceptible membrane staining is detectedin more than 10% of the tumor cells. The cells are only stained in partof their membrane.

[0785] Score 2+—a weak to moderate complete membrane staining isobserved in more than 10% of the tumor cells.

[0786] Score 3+—a moderate to strong complete membrane staining isobserved in more than 10% of the tumor cells.

[0787] Those tumors with 0 or 1+ scores for TAT polypeptide expressionmay be characterized as not overexpressing TAT, whereas those tumorswith 2+ or 3+ scores may be characterized as overexpressing TAT.

[0788] Alternatively, or additionally, FISH assays such as the INFORM®(sold by Ventana, Ariz.) or PATHVISION® (Vysis, Ill.) may be carried outon formalin-fixed, paraffin-embedded tumor tissue to determine theextent (if any) of TAT overexpression in the tumor.

[0789] TAT overexpression or amplification may be evaluated using an invivo diagnostic assay, e.g., by administering a molecule (such as anantibody, oligopeptide or organic molecule) which binds the molecule tobe detected and is tagged with a detectable label (e.g., a radioactiveisotope or a fluorescent label) and externally scanning the patient forlocalization of the label.

[0790] As described above, the anti-TAT antibodies, oligopeptides andorganic molecules of the invention have various non-therapeuticapplications. The anti-TAT antibodies, oligopeptides and organicmolecules of the present invention can be useful for diagnosis andstaging of TAT polypeptide-expressing cancers (e.g., in radioimaging).The antibodies, oligopeptides and organic molecules are also useful forpurification or immunoprecipitation of TAT polypeptide from cells, fordetection and quantitation of TAT polypeptide in vitro, e.g., in anELISA or a Western blot, to kill and eliminate TAT-expressing cells froma population of mixed cells as a step in the purification of othercells.

[0791] Currently, depending on the stage of the cancer, cancer treatmentinvolves one or a combination of the following therapies: surgery toremove the cancerous tissue, radiation therapy, and chemotherapy.Anti-TAT antibody, oligopeptide or organic molecule therapy may beespecially desirable in elderly patients who do not tolerate thetoxicity and side effects of chemotherapy well and in metastatic diseasewhere radiation therapy has limited usefulness. The tumor targetinganti-TAT antibodies, oligopeptides and organic molecules of theinvention are useful to alleviate TAT-expressing cancers upon initialdiagnosis of the disease or during relapse. For therapeuticapplications, the anti-TAT antibody, oligopeptide or organic moleculecan be used alone, or in combination therapy with, e.g., hormones,antiangiogens, or radiolabelled compounds, or with surgery, cryotherapy,and/or radiotherapy. Anti-TAT antibody, oligopeptide or organic moleculetreatment can be administered in conjunction with other forms ofconventional therapy, either consecutively with, pre- orpost-conventional therapy. Chemotherapeutic drugs such as TAXOTERE®(docetaxel), TAXOL® (palictaxel), estramustine and mitoxantrone are usedin treating cancer, in particular, in good risk patients. In the presentmethod of the invention for treating or alleviating cancer, the cancerpatient can be administered anti-TAT antibody, oligopeptide or organicmolecule in conjuction with treatment with the one or more of thepreceding chemotherapeutic agents. In particular, combination therapywith palictaxel and modified derivatives (see, e.g., EP0600517) iscontemplated. The anti-TAT antibody, oligopeptide or organic moleculewill be administered with a therapeutically effective dose of thechemotherapeutic agent. In another embodiment, the anti-TAT antibody,oligopeptide or organic molecule is administered in conjunction withchemotherapy to enhance the activity and efficacy of thechemotherapeutic agent, e.g., paclitaxel. The Physicians' Desk Reference(PDR) discloses dosages of these agents that have been used in treatmentof various cancers. The dosing regimen and dosages of theseaforementioned chemotherapeutic drugs that are therapeutically effectivewill depend on the particular cancer being treated, the extent of thedisease and other factors familiar to the physician of skill in the artand can be determined by the physician.

[0792] In one particular embodiment, a conjugate comprising an anti-TATantibody, oligopeptide or organic molecule conjugated with a cytotoxicagent is administered to the patient. Preferably, the immunoconjugatebound to the TAT protein is internalized by the cell, resulting inincreased therapeutic efficacy of the immunoconjugate in killing thecancer cell to which it binds. In a preferred embodiment, the cytotoxicagent targets or interferes with the nucleic acid in the cancer cell.Examples of such cytotoxic agents are described above and includemaytansinoids, calicheamicins, ribonucleases and DNA endonucleases.

[0793] The anti-TAT antibodies, oligopeptides, organic molecules ortoxin conjugates thereof are administered to a human patient, in accordwith known methods, such as intravenous administration, e.g.,, as abolus or by continuous infusion over a period of time, by intramuscular,intraperitoneal, intracerobrospinal, subcutaneous, intra-articular,intrasynovial, intrathecal, oral, topical, or inhalation routes.Intravenous or subcutaneous administration of the antibody, oligopeptideor organic molecule is preferred.

[0794] Other therapeutic regimens may be combined with theadministration of the anti-TAT antibody, oligopeptide or organicmolecule. The combined administration includes co-administration, usingseparate formulations or a single pharmaceutical formulation, andconsecutive administration in either order, wherein preferably there isa time period while both (or all) active agents simultaneously exerttheir biological activities. Preferably such combined therapy results ina synergistic therapeutic effect.

[0795] It may also be desirable to combine administration of theanti-TAT antibody or antibodies, oligopeptides or organic molecules,with administration of an antibody directed against another tumorantigen associated with the particular cancer.

[0796] In another embodiment, the therapeutic treatment methods of thepresent invention involves the combined administration of an anti-TATantibody (or antibodies), oligopeptides or organic molecules and one ormore chemotherapeutic agents or growth inhibitory agents, includingco-administration of cocktails of different chemotherapeutic agents.Chemotherapeutic agents include estramustine phosphate, prednimustine,cisplatin, 5-fluorouracil, melphalan, cyclophosphamide, hydroxyurea andhydroxyureataxanes (such as paclitaxel and doxetaxel) and/oranthracycline antibiotics. Preparation and dosing schedules for suchchemotherapeutic agents may be used according to manufacturers'instructions or as determined empirically by the skilled practitioner.Preparation and dosing schedules for such chemotherapy are alsodescribed in Chemotherapy Service Ed., M. C. Perry, Williams & Wilkins,Baltimore, Md. (1992).

[0797] The antibody, oligopeptide or organic molecule may be combinedwith an anti-hormonal compound; e.g., an anti-estrogen compound such astamoxifen; an anti-progesterone such as onapristone (see, EP 616 812);or an anti-androgen such as flutamide, in dosages known for suchmolecules. Where the cancer to be treated is androgen independentcancer, the patient may previously have been subjected to anti-androgentherapy and, after the cancer becomes androgen independent, the anti-TATantibody, oligopeptide or organic molecule (and optionally other agentsas described herein) may be administered to the patient.

[0798] Sometimes, it may be beneficial to also co-administer acardioprotectant (to prevent or reduce myocardial dysfunction associatedwith the therapy) or one or more cytokines to the patient. In additionto the above therapeutic regimes, the patient may be subjected tosurgical removal of cancer cells and/or radiation therapy, before,simultaneously with, or post antibody, oligopeptide or organic moleculetherapy. Suitable dosages for any of the above co-administered agentsare those presently used and may be lowered due to the combined action(synergy) of the agent and anti-TAT antibody, oligopeptide or organicmolecule.

[0799] For the prevention or treatment of disease, the dosage and modeof administration will be chosen by the physician according to knowncriteria. The appropriate dosage of antibody, oligopeptide or organicmolecule will depend on the type of disease to be treated, as definedabove, the severity and course of the disease, whether the antibody,oligopeptide or organic molecule is administered for preventive ortherapeutic purposes, previous therapy, the patient's clinical historyand response to the antibody, oligopeptide or organic molecule, and thediscretion of the attending physician. The antibody, oligopeptide ororganic molecule is suitably administered to the patient at one time orover a series of treatments. Preferably, the antibody, oligopeptide ororganic molecule is administered by intravenous infusion or bysubcutaneous injections. Depending on the type and severity of thedisease, about 1 μg/kg to about 50 mg/kg body weight (e.g., about 0.1-15mg/kg/dose) of antibody can be an initial candidate dosage foradministration to the patient, whether, for example, by one or moreseparate administrations, or by continuous infusion. A dosing regimencan comprise administering an initial loading dose of about 4 mg/kg,followed by a weekly maintenance dose of about 2 mg/kg of the anti-TATantibody. However, other dosage regimens may be useful. A typical dailydosage might range from about 1 μg/kg to 100 mg/kg or more, depending onthe factors mentioned above. For repeated administrations over severaldays or longer, depending on the condition, the treatment is sustaineduntil a desired suppression of disease symptoms occurs. The progress ofthis therapy can be readily monitored by conventional methods and assaysand based on criteria known to the physician or other persons of skillin the art.

[0800] Aside from administration of the antibody protein to the patient,the present application contemplates administration of the antibody bygene therapy. Such administration of nucleic acid encoding the antibodyis encompassed by the expression “administering a therapeuticallyeffective amount of an antibody”. See, for example, WO96/07321 publishedMar. 14, 1996 concerning the use of gene therapy to generateintracellular antibodies.

[0801] There are two major approaches to getting the nucleic acid(optionally contained in a vector) into the patient's cells; in vivo andex vivo. For in vivo delivery the nucleic acid is injected directly intothe patient, usually at the site where the antibody is required. For exvivo treatment, the patient's cells are removed, the nucleic acid isintroduced into these isolated cells and the modified cells areadministered to the patient either directly or, for example,encapsulated within porous membranes which are implanted into thepatient (see, e.g., U.S. Pat. Nos. 4,892,538 and 5,283,187). There are avariety of techniques available for introducing nucleic acids intoviable cells. The techniques vary depending upon whether the nucleicacid is transferred into cultured cells in vitro, or in vivo in thecells of the intended host. Techniques suitable for the transfer ofnucleic acid into mammalian cells in vitro include the use of liposomes,electroporation, microinjection, cell fusion, DEAE-dextran, the calciumphosphate precipitation method, etc. A commonly used vector for ex vivodelivery of the gene is a retroviral vector.

[0802] The currently preferred in vivo nucleic acid transfer techniquesinclude transfection with viral vectors (such as adenovirus, Herpessimplex I virus, or adeno-associated virus) and lipid-based systems(useful lipids for lipid-mediated transfer of the gene are DOTMA, DOPEand DC-Chol, for example). For review of the currently known genemarking and gene therapy protocols see Anderson et al., Science256:808-813 (1992). See also WO 93/25673 and the references citedtherein.

[0803] The anti-TAT antibodies of the invention can be in the differentforms encompassed by the definition of “antibody” herein. Thus, theantibodies include full length or intact antibody, antibody fragments,native sequence antibody or amino acid variants, humanized, chimeric orfusion antibodies, immunoconjugates, and functional fragments thereof.In fusion antibodies an antibody sequence is fused to a heterologouspolypeptide sequence. The antibodies can be modified in the Fc region toprovide desired effector functions. As discussed in more detail in thesections herein, with the appropriate Fc regions, the naked antibodybound on the cell surface can induce cytotoxicity, e.g., viaantibody-dependent cellular cytotoxicity (ADCC) or by recruitingcomplement in complement dependent cytotoxicity, or some othermechanism. Alternatively, where it is desirable to eliminate or reduceeffector function, so as to minimize side effects or therapeuticcomplications, certain other Fc regions may be used.

[0804] In one embodiment, the antibody competes for binding or bindsubstantially to, the same epitope as the antibodies of the invention.Antibodies having the biological characteristics of the present anti-TATantibodies of the invention are also contemplated, specificallyincluding the in vivo tumor targeting and any cell proliferationinhibition or cytotoxic characteristics.

[0805] Methods of producing the above antibodies are described in detailherein.

[0806] The present anti-TAT antibodies, oligopeptides and organicmolecules are useful for treating a TAT-expressing cancer or alleviatingone or more symptoms of the cancer in a mammal. Such a cancer includesprostate cancer, cancer of the urinary tract, lung cancer, breastcancer, colon cancer and ovarian cancer, more specifically, prostateadenocarcinoma, renal cell carcinomas, colorectal adenocarcinomas, lungadenocarcinomas, lung squamous cell carcinomas, and pleuralmesothelioma. The cancers encompass metastatic cancers of any of thepreceding. The antibody, oligopeptide or organic molecule is able tobind to at least a portion of the cancer cells that express TATpolypeptide in the mammal. In a preferred embodiment, the antibody,oligopeptide or organic molecule is effective to destroy or killTAT-expressing tumor cells or inhibit the growth of such tumor cells, invitro or in vivo, upon binding to TAT polypeptide on the cell. Such anantibody includes a naked anti-TAT antibody (not conjugated to anyagent). Naked antibodies that have cytotoxic or cell growth inhibitionproperties can be further harnessed with a cytotoxic agent to renderthem even more potent in tumor cell destruction. Cytotoxic propertiescan be conferred to an anti-TAT antibody by, e.g., conjugating theantibody with a cytotoxic agent, to form an immunoconjugate as describedherein. The cytotoxic agent or a growth inhibitory agent is preferably asmall molecule. Toxins such as calicheamicin or a maytansinoid andanalogs or derivatives thereof, are preferable.

[0807] The invention provides a composition comprising an anti-TATantibody, oligopeptide or organic molecule of the invention, and acarrier. For the purposes of treating cancer, compositions can beadministered to the patient in need of such treatment, wherein thecomposition can comprise one or more anti-TAT antibodies present as animmunoconjugate or as the naked antibody. In a further embodiment, thecompositions can comprise these antibodies, oligopeptides or organicmolecules in combination with other therapeutic agents such as cytotoxicor growth inhibitory agents, including chemotherapeutic agents. Theinvention also provides formulations comprising an anti-TAT antibody,oligopeptide or organic molecule of the invention, and a carrier. In oneembodiment, the formulation is a therapeutic formulation comprising apharmaceutically acceptable carrier.

[0808] Another aspect of the invention is isolated nucleic acidsencoding the anti-TAT antibodies. Nucleic acids encoding both the H andL chains and especially the hypervariable region residues, chains whichencode the native sequence antibody as well as variants, modificationsand humanized versions of the antibody, are encompassed.

[0809] The invention also provides methods useful for treating a TATpolypeptide-expressing cancer or alleviating one or more symptoms of thecancer in a mammal, comprising administering a therapeutically effectiveamount of an anti-TAT antibody, oligopeptide or organic molecule to themammal. The antibody, oligopeptide or organic molecule therapeuticcompositions can be administered short term (acute) or chronic, orintermittent as directed by physician. Also provided are methods ofinhibiting the growth of, and killing a TAT polypeptide-expressing cell.

[0810] The invention also provides kits and articles of manufacturecomprising at least one anti-TAT antibody, oligopeptide or organicmolecule. Kits containing anti-TAT antibodies, oligopeptides or organicmolecules find use, e.g., for TAT cell killing assays, for purificationor immunoprecipitation of TAT polypeptide from cells. For example, forisolation and purification of TAT, the kit can contain an anti-TATantibody, oligopeptide or organic molecule coupled to beads (e.g.,sepharose beads). Kits can be provided which contain the antibodies,oligopeptides or organic molecules for detection and quantitation of TATin vitro, e.g., in an ELISA or a Western blot. Such antibody,oligopeptide or organic molecule useful for detection may be providedwith a label such as a fluorescent or radiolabel.

[0811] L. Articles of Manufacture and Kits

[0812] Another embodiment of the invention is an article of manufacturecontaining materials useful for the treatment of anti-TAT expressingcancer. The article of manufacture comprises a container and a label orpackage insert on or associated with the container. Suitable containersinclude, for example, bottles, vials, syringes, etc. The containers maybe formed from a variety of materials such as glass or plastic. Thecontainer holds a composition which is effective for treating the cancercondition and may have a sterile access port (for example the containermay be an intravenous solution bag or a vial having a stopper pierceableby a hypodermic injection needle). At least one active agent in thecomposition is an anti-TAT antibody, oligopeptide or organic molecule ofthe invention. The label or package insert indicates that thecomposition is used for treating cancer. The label or package insertwill further comprise instructions for administering the antibody,oligopeptide or organic molecule composition to the cancer patient.Additionally, the article of manufacture may further comprise a secondcontainer comprising a pharmaceutically-acceptable buffer, such asbacteriostatic water for injection (BWFI), phosphate-buffered saline,Ringer's solution and dextrose solution. It may further include othermaterials desirable from a commercial and user standpoint, includingother buffers, diluents, filters, needles, and syringes.

[0813] Kits are also provided that are useful for various purposes ,e.g., for TAT-expressing cell killing assays, for purification orimmunoprecipitation of TAT polypeptide from cells. For isolation andpurification of TAT polypeptide, the kit can contain an anti-TATantibody, oligopeptide or organic molecule coupled to beads (e.g.,sepharose beads). Kits can be provided which contain the antibodies,oligopeptides or organic molecules for detection and quantitation of TATpolypeptide in vitro, e.g., in an ELISA or a Western blot. As with thearticle of manufacture, the kit comprises a container and a label orpackage insert on or associated with the container. The container holdsa composition comprising at least one anti-TAT antibody, oligopeptide ororganic molecule of the invention. Additional containers may be includedthat contain, e.g., diluents and buffers, control antibodies. The labelor package insert may provide a description of the composition as wellas instructions for the intended in vitro or diagnostic use.

[0814] M. Uses for TAT Polypeptides and TAT-Polypeptide Encoding NucleicAcids

[0815] Nucleotide sequences (or their complement) encoding TATpolypeptides have various applications in the art of molecular biology,including uses as hybridization probes, in chromosome and gene mappingand in the generation of anti-sense RNA and DNA probes. TAT-encodingnucleic acid will also be useful for the preparation of TAT polypeptidesby the recombinant techniques described herein, wherein those TATpolypeptides may find use, for example, in the preparation of anti-TATantibodies as described herein.

[0816] The full-length native sequence TAT gene, or portions thereof,may be used as hybridization probes for a cDNA library to isolate thefull-length TAT cDNA or to isolate still other cDNAs (for instance,those encoding naturally-occurring variants of TAT or TAT from otherspecies) which have a desired sequence identity to the native TATsequence disclosed herein. Optionally, the length of the probes will beabout 20 to about 50 bases. The hybridization probes may be derived fromat least partially novel regions of the full length native nucleotidesequence wherein those regions may be determined without undueexperimentation or from genomic sequences including promoters, enhancerelements and introns of native sequence TAT. By way of example, ascreening method will comprise isolating the coding region of the TATgene using the known DNA sequence to synthesize a selected probe ofabout 40 bases. Hybridization probes may be labeled by a variety oflabels, including radionucleotides such as ³²P or ³⁵S, or enzymaticlabels such as alkaline phosphatase coupled to the probe viaavidin/biotin coupling systems. Labeled probes having a sequencecomplementary to that of the TAT gene of the present invention can beused to screen libraries of human cDNA, genomic DNA or mRNA to determinewhich members of such libraries the probe hybridizes to. Hybridizationtechniques are described in further detail in the Examples below. AnyEST sequences disclosed in the present application may similarly beemployed as probes, using the methods disclosed herein.

[0817] Other useful fragments of the TAT-encoding nucleic acids includeantisense or sense oligonucleotides comprising a singe-stranded nucleicacid sequence (either RNA or DNA) capable of binding to target TAT mRNA(sense) or TAT DNA (antisense) sequences. Antisense or senseoligonucleotides, according to the present invention, comprise afragment of the coding region of TAT DNA. Such a fragment generallycomprises at least about 14 nucleotides, preferably from about 14 to 30nucleotides. The ability to derive an antisense or a senseoligonucleotide, based upon a cDNA sequence encoding a given protein isdescribed in, for example, Stein and Cohen (Cancer Res. 48:2659, 1988)and van der Krol et al. (BioTechniques 6:958, 1988).

[0818] Binding of antisense or sense oligonucleotides to target nucleicacid sequences results in the formation of duplexes that blocktranscription or translation of the target sequence by one of severalmeans, including enhanced degradation of the duplexes, prematuretermination of transcription or translation, or by other means. Suchmethods are encompassed by the present invention. The antisenseoligonucleotides thus may be used to block expression of TAT proteins,wherein those TAT proteins may play a role in the induction of cancer inmammals. Antisense or sense oligonucleotides further compriseoligonucleotides having modified sugar-phosphodiester backbones (orother sugar linkages, such as those described in WO 91/06629) andwherein such sugar linkages are resistant to endogenous nucleases. Sucholigonucleotides with resistant sugar linkages are stable in vivo (i.e.,capable of resisting enzymatic degradation) but retain sequencespecificity to be able to bind to target nucleotide sequences.

[0819] Preferred intragenic sites for antisense binding include theregion incorporating the translation initiation/start codon(5′-AUG/5′-ATG) or termination/stop codon (5′-UAA, 5′-UAG and5-UGA/5′-TAA, 5′-TAG and 5′-TGA) of the open reading frame (ORF) of thegene. These regions refer to a portion of the mRNA or gene thatencompasses from about 25 to about 50 contiguous nucleotides in eitherdirection (i.e., 5′ or 3′) from a translation initiation or terminationcodon. Other preferred regions for antisense binding include: introns;exons; intron-exon junctions; the open reading frame (ORF) or “codingregion,” which is the region between the translation initiation codonand the translation termination codon; the 5′ cap of an mRNA whichcomprises an N7-methylated guanosine residue joined to the 5′-mostresidue of the mRNA via a 5′-5′ triphosphate linkage and includes 5′ capstructure itself as well as the first 50 nucleotides adjacent to thecap; the 5′ untranslated region (5′UTR), the portion of an mRNA in the5′ direction from the translation initiation codon, and thus includingnucleotides between the 5′ cap site and the translation initiation codonof an mRNA or corresponding nucleotides on the gene; and the 3′untranslated region (3′UTR), the portion of an mRNA in the 3′ directionfrom the translation termination codon, and thus including nucleotidesbetween the translation termination codon and 3′ end of an mRNA orcorresponding nucleotides on the gene.

[0820] Specific examples of preferred antisense compounds useful forinhibiting expression of TAT proteins include oligonucleotidescontaining modified backbones or non-natural internucleoside linkages.Oligonucleotides having modified backbones include those that retain aphosphorus atom in the backbone and those that do not have a phosphorusatom in the backbone. For the purposes of this specification, and assometimes referenced in the art, modified oligonucleotides that do nothave a phosphorus atom in their internucleoside backbone can also beconsidered to be oligonucleosides. Preferred modified oligonucleotidebackbones include, for example, phosphorothioates, chiralphosphorothioates, phosphorodithioates, phosphotriesters,aminoalkylphosphotri-esters, methyl and other alkyl phosphonatesincluding 3′-alkylene phosphonates, 5′-alkylene phosphonates and chiralphosphonates, phosphinates, phosphoramidates including 3′-aminophosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates,thionoalkylphosphonates, thionoalkylphosphotriesters, selenophosphatesand borano-phosphates having normal 3′-5′ linkages, 2′-5′ linked analogsof these, and those having inverted polarity wherein one or moreinternucleotide linkages is a 3′ to 3′, 5′ to 5′ or 2′ to 2′ linkage.Preferred oligonucleotides having inverted polarity comprise a single 3′to 3′ linkage at the 3′-most internucleotide linkage i.e. a singleinverted nucleoside residue which may be abasic (the nucleobase ismissing or has a hydroxyl group in place thereof). Various salts, mixedsalts and free acid forms are also included. Representative UnitedStates patents that teach the preparation of phosphorus-containinglinkages include, but are not limited to, U.S. Pat. Nos.: 3,687,808;4,469,863; 4,476,301; 5,023,243; 5,177,196; 5,188,897; 5,264,423;5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939;5,453,496; 5,455,233; 5,466,677; 5,476,925; 5,519,126; 5,536,821;5,541,306; 5,550,111; 5,563,253; 5,571,799; 5,587,361; 5,194,599;5,565,555; 5,527,899; 5,721,218; 5,672,697 and 5,625,050, each of whichis herein incorporated by reference.

[0821] Preferred modified oligonucleotide backbones that do not includea phosphorus atom therein have backbones that are formed by short chainalkyl or cycloalkyl internucleoside linkages, mixed heteroatom and alkylor cycloalkyl internucleoside linkages, or one or more short chainheteroatomic or heterocyclic internucleoside linkages. These includethose having morpholino linkages (formed in part from the sugar portionof a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfonebackbones; formacetyl and thioformacetyl backbones; methylene formacetyland thioformacetyl backbones; riboacetyl backbones; alkene containingbackbones; sulfamate backbones; methyleneimino and methylenehydrazinobackbones; sulfonate and sulfonamide backbones; amide backbones; andothers having mixed N, O, S and CH.sub.2 component parts. RepresentativeUnited States patents that teach the preparation of sucholigonucleosides include, but are not limited to,. U.S. Pat. Nos.: 55,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033;5,264,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967;5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,610,289;5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312;5,633,360; 5,677,437; 5,792,608; 5,646,269 and 5,677,439, each of whichis herein incorporated by reference.

[0822] In other preferred antisense oligonucleotides, both the sugar andthe internucleoside linkage, i.e., the backbone, of the nucleotide unitsare replaced with novel groups. The base units are maintained forhybridization with an appropriate nucleic acid target compound. One sucholigomeric compound, an oligonucleotide mimetic that has been shown tohave excellent hybridization properties, is referred to as a peptidenucleic acid (PNA). In PNA compounds, the sugar-backbone of anoligonucleotide is replaced with an amide containing backbone, inparticular an aminoethylglycine backbone. The nucleobases are retainedand are bound directly or indirectly to aza nitrogen atoms of the amideportion of the backbone. Representative United States patents that teachthe preparation of PNA compounds include, but are not limited to, U.S.Pat. Nos.: 5,539,082; 5,714,331; and 5,719,262, each of which is hereinincorporated by reference. Further teaching of PNA compounds can befound in Nielsen et al., Science, 1991, 254, 1497-1500.

[0823] Preferred antisense oligonucleotides incorporate phosphorothioatebackbones and/or heteroatom backbones, and in particular —CH₂—NH—O—CH₂—,—CH₂—N(CH₃)—O—CH₂—[known as a methylene (methylimino) or MMI backbone],—CH—O—N(CH₃)—CH₂—, —CH₂—N(CH₃)—N(CH₃)—CH₂—and —O—N(CH₃)—CH₂—CH₂—[whereinthe native phosphodiester backbone is represented as —O—P—O—CH₂—]described in the above referenced U.S. Pat. No. 5,489,677, and the amidebackbones of the above referenced U.S. Pat. No.5,602,240. Also preferredare antisense oligonucleotides having morpholino backbone structures ofthe above-referenced U.S. Pat. No. 5,034,506.

[0824] Modified oligonucleotides may also contain one or moresubstituted sugar moieties. Preferred oligonucleotides comprise one ofthe following at the 2′ position: OH; F; O-alkyl, S-alkyl, or N-alkyl;O-alkenyl, S-alkeynyl, or N-alkenyl; O-alkynyl, S-alkynyl or N-alkynyl;or O-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl may besubstituted or unsubstituted C₁ to C₁₀ alkyl or C₂ to C₁₀ alkenyl andalkynyl. Particularly preferred are O[(CH₂)_(n)O]_(m)CH₃,O(CH₂)_(n)OCH₃, O(CH₂)_(n)NH₂, O(CH₂)_(n)CH₃, O(CH₂)_(n)ONH₂, andO(CH₂)_(n)ON[(CH₂)_(n)CH₃)]₂, where n and m are from 1 to about 10.Other preferred antisense oligonucleotides comprise one of the followingat the 2′ position: C₁ to C₁₀ lower alkyl, substituted lower alkyl,alkenyl, alkynyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH₃,OCN, Cl, Br, CN, CF₃, OCF₃, SOCH₃, SO₂ CH₃, ONO₂, NO₂, N₃, NH₂,heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino,substituted silyl, an RNA cleaving group, a reporter group, anintercalator, a group for improving the pharmacokinetic properties of anoligonucleotide, or a group for improving the pharmacodynamic propertiesof an oligonucleotide, and other substituents having similar properties.A preferred modification includes 2′-methoxyethoxy (2′-O—CH₂CH₂OCH₃,also known as 2′-O-(2-methoxyethyl) or 2′-MOE) (Martin et al., Helv.Chim. Acta, 1995, 78, 486-504) i.e., an alkoxyalkoxy group. A furtherpreferred modification includes 2′-dimethylaminooxyethoxy, i.e., aO(CH₂)₂ON(CH₃)₂ group, also known as 2′-DMAOE, as described in exampleshereinbelow, and 2′-dimethylaminoethoxyethoxy (also known in the art as2′-O-dimethylaminoethoxyethyl or 2′-DMAEOE), i.e.,2′-O—CH₂—O—CH₂—N(CH₂).

[0825] A further prefered modification includes Locked Nucleic Acids(LNAs) in which the 2′-hydroxyl group is linked to the 3′ or 4′ carbonatom of the sugar ring thereby forming a bicyclic sugar moiety. Thelinkage is preferably a methelyne (—CH₂—)_(n) group bridging the 2′oxygen atom and the 4′ carbon atom wherein n is 1or 2. LNAs andpreparation thereof are described in WO 98/39352 and WO 99/14226.

[0826] Other preferred modifications include 2′-methoxy(2′-O—CH₃),2′-aminopropoxy (2′-OCH₂CH₂CH₂NH₂), 2′-allyl (2′-CH₂—CH═CH₂),2′-O-allyl (2′-O—CH₂—CH═CH₂) and 2′-fluoro (2′-F). The 2′-modificationmay be in the arabino (up) position or ribo (down) position. A preferred2′-arabino modification is 2′-F. Similar modifications may also be madeat other positions on the oligonucleotide, particularly the 3′ positionof the sugar on the 3′ terminal nucleotide or in 2′-5′ linkedoligonucleotides and the 5′ position of 5′ terminal nucleotide.Oligonucleotides may also have sugar mimetics such as cyclobutylmoieties in place of the pentofuranosyl sugar. Representative UnitedStates patents that teach the preparation of such modified sugarstructures include, but are not limited to, U.S. Pat. Nos. 4,981,957;5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786;5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909;5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633;5,792,747; and 5,700,920, each of which is herein incorporated byreference in its entirety.

[0827] Oligonucleotides may also include nucleobase (often referred toin the art simply as “base”) modifications or substitutions. As usedherein, “unmodified” or “natural” nucleobases include the purine basesadenine (A) and guanine (G), and the pyrimidine bases thymine (T),cytosine (C) and uracil (U). Modified nucleobases include othersynthetic and natural nucleobases such as 5-methylcytosine (5-me-C),5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine,6-methyl and other alkyl derivatives of adenine and guanine, 2-propyland other alkyl derivatives of adenine and guanine, 2-thiouracil,2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl(—C≡C—CH₃ or —CH₂—C≡CH) uracil and cytosine and other alkynylderivatives of pyrimidine bases, 6-azo uracil, cytosine and thymine,5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol,8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines,5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituteduracils and cytosines, 7-methylguanine and 7-methyladenine, 2-F-adenine,2-amino-adenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and7-deazaadenine and 3-deazaguanine and 3-deazaadenine. Further modifiednucleobases include tricyclic pyrimidines such as phenoxazine cytidine(1H-pyrimido[5,4-b][1,4]benzoxazin-2(3H)-one), phenothiazine cytidine(1H-pyrimido[5,4-b][1,4]benzothiazin-2(3H)-one), G-clamps such as asubstituted phenoxazine cytidine (e.g.9-(2-aminoethoxy)-H-pyrimido[5,4-b][1,4]benzoxazin-2(3H)-one), carbazolecytidine (2H-pyrimido[4,5-b]indol-2-one), pyridoindole cytidine(H-pyrido[3′,2′:4,5]pyrrolo[2,3-d]pyrimidin-2-one). Modified nucleobasesmay also include those in which the purine or pyrimidine base isreplaced with other heterocycles, for example 7-deaza-adenine,7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucleobasesinclude those disclosed in U.S. Pat. No. 3,687,808, those disclosed inThe Concise Encyclopedia Of Polymer Science And Engineering, pages858-859, Kroschwitz, J. I., ed. John Wiley & Sons, 1990, and thosedisclosed by Englisch et al., Angewandte Chemie, International Edition,1991, 30, 613. Certain of these nucleobases are particularly useful forincreasing the binding affinity of the oligomeric compounds of theinvention. These include 5-substituted pyrimidines, 6-azapyrimidines andN-2, N-6 and O-6 substituted purines, including 2-aminopropyladenine,5-propynyluracil and 5-propynylcytosine. 5-methylcytosine substitutionshave been shown to increase nucleic acid duplex stability by0.6-1.2.degree. C. (Sanghvi et al, Antisense Research and Applications,CRC Press, Boca Raton, 1993, pp. 276-278) and are preferred basesubstitutions, even more particularly when combined with2′-O-methoxyethyl sugar modifications. Representative United Statespatents that teach the preparation of modified nucleobases include, butare not limited to: U.S. Pat. No. 3,687,808, as well as U.S. Pat. Nos.:4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272;5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540;5,587,469; 5,594,121,5,596,091; 5,614,617; 5,645,985; 5,830,653;5,763,588; 6,005,096; 5,681,941 and 5,750,692, each of which is hereinincorporated by reference.

[0828] Another modification of antisense oligonucleotides chemicallylinking to the oligonucleotide one or more moieties or conjugates whichenhance the activity, cellular distribution or cellular uptake of theoligonucleotide. The compounds of the invention can include conjugategroups covalently bound to functional groups such as primary orsecondary hydroxyl groups. Conjugate groups of the invention includeintercalators, reporter molecules, polyamines, polyamides, polyethyleneglycols, polyethers, groups that enhance the pharmacodynamic propertiesof oligomers, and groups that enhance the pharmacokinetic properties ofoligomers. Typical conjugates groups include cholesterols, lipids,cation lipids, phospholipids, cationic phospholipids, biotin, phenazine,folate, phenanthridine, anthraquinone, acridine, fluoresceins,rhodamines, coumarins, and dyes. Groups that enhance the pharmacodynamicproperties, in the context of this invention, include groups thatimprove oligomer uptake, enhance oligomer resistance to degradation,and/or strengthen sequence-specific hybridization with RNA. Groups thatenhance the pharmacokinetic properties, in the context of thisinvention, include groups that improve oligomer uptake, distribution,metabolism or excretion. Conjugate moieties include but are not limitedto lipid moieties such as a cholesterol moiety (Letsinger et al., Proc.Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan etal., Bioorg. Med. Chem. Let., 1994, 4, 1053-1060), a thioether, e.g.,hexyl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660,306-309; Manoharan et al., Bioorg. Med. Chem. Let., 1993, 3, 2765-2770),a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20,533-538), an aliphatic chain, e.g., dodecandiol or undecyl residues(Saison-Behmoaras et al., EMBO J., 1991, 10, 1111-1118; Kabanov et al.,FEBS Lett., 1990, 259, 327-330; Svinarchuk et al., Biochimie, 1993, 75,49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol ortriethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate(Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654; Shea et al.,Nucl. Acids Res., 1990, 18, 3777-3783), a polyamine or a polyethyleneglycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14,969-973), or adamantane acetic acid (Manoharan et al., TetrahedronLett., 1995, 36, 3651-3654), a palmityl moiety (Mishra et al., Biochim.Biophys. Acta, 1995, 1264, 229-237), or an octadecylamine orhexylamino-carbonyl-oxycholesterol moiety. Oligonucleotides of theinvention may also be conjugated to active drug substances, for example,aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fenbufen,ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine,2,3,5-triiodobenzoic acid, flufenamic acid, folinic acid, abenzothiadiazide, chlorothiazide, a diazepine, indomethicin, abarbiturate, a cephalosporin, a sulfa drug, an antidiabetic, anantibacterial or an antibiotic. Oligonucleotide-drug conjugates andtheir preparation are described in U.S. patent application Ser. No.09/334,130 (filed Jun. 15, 1999) and U.S. Pat. Nos.: 4,828,979;4,948,882; 5,218,105; 5,525,465; 5,541,313; 5,545,730; 5,552,538;5,578,717,5,580,731; 5,580,731; 5,591,584; 5,109,124; 5,118,802;5,138,045; 5,414,077; 5,486,603; 5,512,439; 5,578,718; 5,608,046;4,587,044; 4,605,735; 4,667,025; 4,762,779; 4,789,737; 4,824,941;4,835,263; 4,876,335; 4,904,582; 4,958,013; 5,082,830; 5,112,963;5,214,136; 5,082,830; 5,112,963; 5,214,136; 5,245,022; 5,254,469;5,258,506; 5,262,536; 5,272,250; 5,292,873; 5,317,098; 5,371,241,5,391,723; 5,416,203, 5,451,463; 5,510,475; 5,512,667; 5,514,785;5,565,552; 5,567,8 1 0; 5,574,142; 5,585,48 1; 5,587,37 1; 5,595,726;5,597,696; 5,599,923; 5,599,928 and 5,688,941, each of which is hereinincorporated by reference.

[0829] It is not necessary for all positions in a given compound to beuniformly modified, and in fact more than one of the aforementionedmodifications may be incorporated in a single compound or even at asingle nucleoside within an oligonucleotide. The present invention alsoincludes antisense compounds which are chimeric compounds. “Chimeric”antisense compounds or “chimeras,” in the context of this invention, areantisense compounds, particularly oligonucleotides, which contain two ormore chemically distinct regions, each made up of at least one monomerunit, i.e., a nucleotide in the case of an oligonucleotide compound.These oligonucleotides typically contain at least one region wherein theoligonucleotide is modified so as to confer upon the oligonucleotideincreased resistance to nuclease degradation, increased cellular uptake,and/or increased binding affinity for the target nucleic acid. Anadditional region of the oligonucleotide may serve as a substrate forenzymes capable of cleaving RNA:DNA or RNA:RNA hybrids. By way ofexample, RNase H is a cellular endonuclease which cleaves the RNA strandof an RNA:DNA duplex. Activation of RNase H, therefore, results incleavage of the RNA target, thereby greatly enhancing the efficiency ofoligonucleotide inhibition of gene expression. Consequently, comparableresults can often be obtained with shorter oligonucleotides whenchimeric oligonucleotides are used, compared to phosphorothioatedeoxyoligonucleotides hybridizing to the same target region. Chimericantisense compounds of the invention may be formed as compositestructures of two or more oligonucleotides, modified oligonucleotides,oligonucleosides and/or oligonucleotide mimetics as described above.Preferred chimeric antisense oligonucleotides incorporate at least one2′ modified sugar (preferably 2′—O—(CH₂)₂—O—CH₃) at the 3′ terminal toconfer nuclease resistance and a region with at least 4 contiguous 2′-Hsugars to confer RNase H activity. Such compounds have also beenreferred to in the art as hybrids or gapmers. Preferred gapmers have aregion of 2′ modified sugars (preferably 2′-O—(CH₂)₂—O—CH₃) at the3′-terminal and at the 5′ terminal separated by at least one regionhaving at least 4 contiguous 2′-H sugars and preferably incorporatephosphorothioate backbone linkages. Representative United States patentsthat teach the preparation of such hybrid structures include, but arenot limited to, U.S. Pat. Nos. 5,013,830; 5,149,797; 5,220,007;5,256,775; 5,366,878; 5,403,711; 5,491,133; 5,565,350; 5,623,065;5,652,355; 5,652,356; and 5,700,922, each of which is hereinincorporated by reference in its entirety.

[0830] The antisense compounds used in accordance with this inventionmay be conveniently and routinely made through the well-known techniqueof solid phase synthesis. Equipment for such synthesis is sold byseveral vendors including, for example, Applied Biosystems (Foster City,Calif.). Any other means for such synthesis known in the art mayadditionally or alternatively be employed. It is well known to usesimilar techniques to prepare oligonucleotides such as thephosphorothioates and alkylated derivatives. The compounds of theinvention may also be admixed, encapsulated, conjugated or otherwiseassociated with other molecules, molecule structures or mixtures ofcompounds, as for example, liposomes, receptor targeted molecules, oral,rectal, topical or other formulations, for assisting in uptake,distribution and/or absorption. Representative United States patentsthat teach the preparation of such uptake, distribution and/orabsorption assisting formulations include, but are not limited to, U.S.Pat. Nos. 5,108,921; 5,354,844; 5,416,016; 5,459,127; 5,521,291;5,543,158; 5,547,932; 5,583,020; 5,591,721; 4,426,330; 4,534,899;5,013,556; 5,108,921; 5,213,804; 5,227,170; 5,264,221; 5,356,633;5,395,619; 5,416,016; 5,417,978; 5,462,854; 5,469,854; 5,512,295;5,527,528; 5,534,259; 5,543,152; 5,556,948; 5,580,575; and 5,595,756,each of which is herein incorporated by reference.

[0831] Other examples of sense orantisense oligonucleotides includethose oligonucleotides which are covalently linked to organic moieties,such as those described in WO 90/10048, and other moieties thatincreases affinity of the oligonucleotide for a target nucleic acidsequence, such as poly-(L-lysine). Further still, intercalating agents,such as ellipticine, and alkylating agents or metal complexes may beattached to sense or antisense oligonucleotides to modify bindingspecificities of the antisense or sense oligonucleotide for the targetnucleotide sequence.

[0832] Antisense or sense oligonucleotides may be introduced into a cellcontaining the target nucleic acid sequence by any gene transfer method,including, for example, Ca

mediated DNA transfection, electroporation, or by using gene transfervectors such as Epstein-Barr virus. In a preferred procedure, anantisense or sense oligonucleotide is inserted into a suitableretroviral vector. A cell containing the target nucleic acid sequence iscontacted with the recombinant retroviral vector, either in vivo or exvivo. Suitable retroviral vectors include, but are not limited to, thosederived from the murine retrovirus M-MuLV, N2 (a retrovirus derived fromM-MuLV), or the double copy vectors designated DCT5A, DCTSB and DCT5C(see WO 90/13641).

[0833] Sense or antisense oligonucleotides also may be introduced into acell containing the target nucleotide sequence by formation of aconjugate with a ligand binding molecule, as described in WO 91/04753.Suitable ligand binding molecules include, but are not limited to, cellsurface receptors, growth factors, other cytokines, or other ligandsthat bind to cell surface receptors. Preferably, conjugation of theligand binding molecule does not substantially interfere with theability of the ligand binding molecule to bind to its correspondingmolecule or receptor, or block entry of the sense or antisenseoligonucleotide or its conjugated version into the cell.

[0834] Alternatively, a sense or an antisense oligonucleotide may beintroduced into a cell containing the target nucleic acid sequence byformation of an oligonucleotide-lipid complex, as described in WO90/10448. The sense or antisense oligonucleotide-lipid complex ispreferably dissociated within the cell by an endogenous lipase.

[0835] Antisense or sense RNA or DNA molecules are generally at leastabout 5 nucleotides in length, alternatively at least about 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100,105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170,175, 180, 185, 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280,290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420,430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560,570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700,710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840,850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980,990, or 1000 nucleotides in length, wherein in this context the term“about” means the referenced nucleotide sequence length plus or minus10% of that referenced length.

[0836] The probes may also be employed in PCR techniques to generate apool of sequences for identification of closely related TAT codingsequences.

[0837] Nucleotide sequences encoding a TAT can also be used to constructhybridization probes for mapping the gene which encodes that TAT and forthe genetic analysis of individuals with genetic disorders. Thenucleotide sequences provided herein may be mapped to a chromosome andspecific regions of a chromosome using known techniques, such as in situhybridization, linkage analysis against known chromosomal markers, andhybridization screening with libraries.

[0838] When the coding sequences for TAT encode a protein which binds toanother protein (example, where the TAT is a receptor), the TAT can beused in assays to identify the other proteins or molecules involved inthe binding interaction. By such methods, inhibitors of thereceptor/ligand binding interaction can be identified. Proteins involvedin such binding interactions can also be used to screen for peptide orsmall molecule inhibitors or agonists of the binding interaction. Also,the receptor TAT can be used to isolate correlative ligand(s). Screeningassays can be designed to find lead compounds that mimic the biologicalactivity of a native TAT or a receptor for TAT. Such screening assayswill include assays amenable to high-throughput screening of chemicallibraries, making them particularly suitable for identifying smallmolecule drug candidates. Small molecules contemplated include syntheticorganic or inorganic compounds. The assays can be performed in a varietyof formats, including protein-protein binding assays, biochemicalscreening assays, immunoassays and cell based assays, which are wellcharacterized in the art.

[0839] Nucleic acids which encode TAT or its modified forms can also beused to generate either transgenic animals or “knock out” animals which,in turn, are useful in the development and screening of therapeuticallyuseful reagents. A transgenic animal (e.g., a mouse or rat) is an animalhaving cells that contain a transgene, which transgene was introducedinto the animal or an ancestor of the animal at a prenatal, e.g., anembryonic stage. A transgene is a DNA which is integrated into thegenome of a cell from which a transgenic animal develops. In oneembodiment, cDNA encoding TAT can be used to clone genomic DNA encodingTAT in accordance with established techniques and the genomic sequencesused to generate transgenic animals that contain cells which express DNAencoding TAT. Methods for generating transgenic animals, particularlyanimals such as mice or rats, have become conventional in the art andare described, for example, in U.S. Pat. Nos. 4,736,866 and 4,870,009.Typically, particular cells would be targeted for TAT transgeneincorporation with tissue-specific enhancers. Transgenic animals thatinclude a copy of a transgene encoding TAT introduced into the germ lineof the animal at an embryonic stage can be used to examine the effect ofincreased expression of DNA encoding TAT. Such animals can be used astester animals for reagents thought to confer protection from, forexample, pathological conditions associated with its overexpression. Inaccordance with this facet of the invention, an animal is treated withthe reagent and a reduced incidence of the pathological condition,compared to untreated animals bearing the transgene, would indicate apotential therapeutic intervention for the pathological condition.

[0840] Alternatively, non-human homologues of TAT can be used toconstruct a TAT “knock out” animal which has a defective or altered geneencoding TAT as a result of homologous recombination between theendogenous gene encoding TAT and altered genomic DNA encoding TATintroduced into an embryonic stem cell of the animal. For example. cDNAencoding TAT can be used to clone genomic DNA encoding TAT in accordancewith established techniques. A portion of the genomic DNA encoding TATcan be deleted or replaced with another gene, such as a gene encoding aselectable marker which can be used to monitor integration. Typically,several kilobases of unaltered flanking DNA (both at the 5′ and 3′ ends)are included in the vector [see e.g., Thomas and Capecchi, Cell, 51:503(1987) for a description of homologous recombination vectors]. Thevector is introduced into an embryonic stem cell line (e.g., byelectroporation) and cells in which the introduced DNA has homologouslyrecombined with the endogenous DNA are selected [see e.g., Li et al.,Cell, 69:915 (1992)]. The selected cells are then injected into ablastocyst of an animal (e.g., a mouse or rat) to form aggregationchimeras [see e.g., Bradley, in Teratocarcinomas and Embryonic StemCells: A Practical Approach, E. J. Robertson, ed. (IRL, Oxford, 1987),pp. 113-1521. A chimeric embryo can then be implanted into a suitablepseudopregnant female foster animal and the embryo brought to term tocreate a “knock out” animal. Progeny harboring the homologouslyrecombined DNA in their germ cells can be identified by standardtechniques and used to breed animals in which all cells of the animalcontain the homologously recombined DNA. Knockout animals can becharacterized for instance, for their ability to defend against certainpathological conditions and for their development of pathologicalconditions due to absence of the TAT polypeptide.

[0841] Nucleic acid encoding the TAT polypeptides may also be used ingene therapy. In gene therapy applications, genes are introduced intocells in order to achieve in vivo synthesis of a therapeuticallyeffective genetic product, for example for replacement of a defectivegene. “Gene therapy” includes both conventional gene therapy where alasting effect is achieved by a single treatment, and the administrationof gene therapeutic agents, which involves the one time or repeatedadministration of a therapeutically effective DNA or mRNA. AntisenseRNAs and DNAs can be used as therapeutic agents for blocking theexpression of certain genes in vivo. It has already been shown thatshort antisense oligonucleotides can be imported into cells where theyact as inhibitors, despite their low intracellular concentrations causedby their restricted uptake by the cell membrane. (Zamecnik et al., Proc.Natl. Acad. Sci. USA 83:4143-4146 [1986]). The oligonucleotides can bemodified to enhance their uptake, e.g. by substituting their negativelycharged phosphodiester groups by uncharged groups.

[0842] There are a variety of techniques available for introducingnucleic acids into viable cells. The techniques vary depending uponwhether the nucleic acid is transferred into cultured cells in vitro, orin vivo in the cells of the intended host. Techniques suitable for thetransfer of nucleic acid into mammalian cells in vitro include the useof liposomes, electroporation, microinjection, cell fusion,DEAE-dextran, the calcium phosphate precipitation method, etc. Thecurrently preferred in vivo gene transfer techniques includetransfection with viral (typically retroviral) vectors and viral coatprotein-liposome mediated transfection (Dzau et al., Trends inBiotechnology 11, 205-210 [1993]). In some situations it is desirable toprovide the nucleic acid source with an agent that targets the targetcells, such as an antibody specific for a cell surface membrane proteinor the target cell, a ligand for a receptor on the target cell, etc.Where liposomes are employed, proteins which bind to a cell surfacemembrane protein associated with endocytosis may be used for targetingand/or to facilitate uptake, e.g. capsid proteins or fragments thereoftropic for a particular cell type, antibodies for proteins which undergointernalization in cycling, proteins that target intracellularlocalization and enhance intracellular half-life. The technique ofreceptor-mediated endocytosis is described, for example, by Wu et al.,J. Biol. Chem. 262, 4429-4432 (1987); and Wagner et al., Proc. Natl.Acad. Sci. USA 87,3410-3414 (1990). For review of gene marking and genetherapy protocols see Anderson et al., Science 256, 808-813 (1992).

[0843] The nucleic acid molecules encoding the TAT polypeptides orfragments thereof described herein are useful for chromosomeidentification. In this regard, there exists an ongoing need to identifynew chromosome markers, since relatively few chromosome markingreagents, based upon actual sequence data are presently available. EachTAT nucleic acid molecule of the present invention can be used as achromosome marker.

[0844] The TAT polypeptides and nucleic acid molecules of the presentinvention may also be used diagnostically for tissue typing, wherein theTAT polypeptides of the present invention may be differentiallyexpressed in one tissue as compared to another, preferably in a diseasedtissue as compared to a normal tissue of the same tissue type. TATnucleic acid molecules will find use for generating probes for PCR,Northern analysis, Southern analysis and Western analysis.

[0845] This invention encompasses methods of screening compounds toidentify those that mimic the TAT polypeptide (agonists) or prevent theeffect of the TAT polypeptide (antagonists). Screening assays forantagonist drug candidates are designed to identify compounds that bindor complex with the TAT polypeptides encoded by the genes identifiedherein, or otherwise interfere with the interaction of the encodedpolypeptides with other cellular proteins, including e.g., inhibitingthe expression of TAT polypeptide from cells. Such screening assays willinclude assays amenable to high-throughput screening of chemicallibraries, making them particularly suitable for identifying smallmolecule drug candidates.

[0846] The assays can be performed in a variety of formats, includingprotein-protein binding assays, biochemical screening assays,immunoassays, and cell-based assays, which are well characterized in theart.

[0847] All assays for antagonists are common in that they call forcontacting the drug candidate with a TAT polypeptide encoded by anucleic acid identified herein under conditions and for a timesufficient to allow these two components to interact.

[0848] In binding assays, the interaction is binding and the complexformed can be isolated or detected in the reaction mixture. In aparticular embodiment, the TAT polypeptide encoded by the geneidentified herein or the drug candidate is immobilized on a solid phase,e.g., on a microtiter plate, by covalent or non-covalent attachments.Non-covalent attachment generally is accomplished by coating the solidsurface with a solution of the TAT polypeptide and drying.Alternatively, an immobilized antibody, e.g., a monoclonal antibody,specific for the TAT polypeptide to be immobilized can be used to anchorit to a solid surface. The assay is performed by adding thenon-immobilized component, which may be labeled by a detectable label,to the immobilized component, e.g., the coated surface containing theanchored component. When the reaction is complete, the non-reactedcomponents are removed, e.g., by washing, and complexes anchored on thesolid surface are detected. When the originally non-immobilizedcomponent carries a detectable label, the detection of label immobilizedon the surface indicates that complexing occurred. Where the originallynon-immobilized component does not carry a label, complexing can bedetected, for example, by using a labeled antibody specifically bindingthe immobilized complex.

[0849] If the candidate compound interacts with but does not bind to aparticular TAT polypeptide encoded by a gene identified herein, itsinteraction with that polypeptide can be assayed by methods well knownfor detecting protein-protein interactions. Such assays includetraditional approaches, such as, e.g., cross-linking,co-immunoprecipitation, and co-purification through gradients orchromatographic columns. In addition, protein-protein interactions canbe monitored by using a yeast-based genetic system described by Fieldsand co-workers (Fields and Song, Nature (London), 340:245-246 (1989);Chien et al., Proc. Natl. Acad. Sci. USA, 88:9578-9582 (1991)) asdisclosed by Chevray and Nathans, Proc. Natl. Acad. Sci. USA, 89:5789-5793 (1991). Many transcriptional activators, such as yeast GAL4,consist of two physically discrete modular domains, one acting as theDNA-binding domain, the other one functioning as thetranscription-activation domain. The yeast expression system describedin the foregoing publications (generally referred to as the “two-hybridsystem”) takes advantage of this property, and employs two hybridproteins, one in which the target protein is fused to the DNA-bindingdomain of GAL4, and another, in which candidate activating proteins arefused to the activation domain. The expression of a GAL1-lacZ reportergene under control of a GAL4-activated promoter depends onreconstitution of GAL4 activity via protein-protein interaction.Colonies containing interacting polypeptides are detected with achromogenic substrate for β-galactosidase. A complete kit (MATCHMAKER™)for identifying protein-protein interactions between two specificproteins using the two-hybrid technique is commercially available fromClontech. This system can also be extended to map protein domainsinvolved in specific protein interactions as well as to pinpoint aminoacid residues that are crucial for these interactions.

[0850] Compounds that interfere with the interaction of a gene encodinga TAT polypeptide identified herein and other intra- or extracellularcomponents can be tested as follows: usually a reaction mixture isprepared containing the product of the gene and the intra- orextracellular component under conditions and for a time allowing for theinteraction and binding of the two products. To test the ability of acandidate compound to inhibit binding, the reaction is run in theabsence and in the presence of the test compound. In addition, a placebomay be added to a third reaction mixture, to serve as positive control.The binding (complex formation) between the test compound and the intra-or extracellular component present in the mixture is monitored asdescribed hereinabove. The formation of a complex in the controlreaction(s) but not in the reaction mixture containing the test compoundindicates that the test compound interferes with the interaction of thetest compound and its reaction partner.

[0851] To assay for antagonists, the TAT polypeptide may be added to acell along with the compound to be screened for a particular activityand the ability of the compound to inhibit the activity of interest inthe presence of the TAT polypeptide indicates that the compound is anantagonist to the TAT polypeptide. Alternatively, antagonists may bedetected by combining the TAT polypeptide and a potential antagonistwith membrane-bound TAT polypeptide receptors or recombinant receptorsunder appropriate conditions for a competitive inhibition assay. The TATpolypeptide can be labeled, such as by radioactivity, such that thenumber of TAT polypeptide molecules bound to the receptor can be used todetermine the effectiveness of the potential antagonist. The geneencoding the receptor can be identified by numerous methods known tothose of skill in the art, for example, ligand panning and FACS sorting.Coligan et al., Current Protocols in Immun., 1(2): Chapter 5 (1991).Preferably, expression cloning is employed wherein polyadenylated RNA isprepared from a cell responsive to the TAT polypeptide and a cDNAlibrary created from this RNA is divided into pools and used totransfect COS cells or other cells that are not responsive to the TATpolypeptide. Transfected cells that are grown on glass slides areexposed to labeled TAT polypeptide. The TAT polypeptide can be labeledby a variety of means including iodination or inclusion of a recognitionsite for a site-specific protein kinase. Following fixation andincubation, the slides are subjected to autoradiographic analysis.Positive pools are identified and sub-pools are prepared andre-transfected using an interactive sub-pooling and re-screeningprocess, eventually yielding a single clone that encodes the putativereceptor.

[0852] As an alternative approach for receptor identification, labeledTAT polypeptide can be photoaffinity-linked with cell membrane orextract preparations that express the receptor molecule. Cross-linkedmaterial is resolved by PAGE and exposed to X-ray film. The labeledcomplex containing the receptor can be excised, resolved into peptidefragments, and subjected to protein micro-sequencing. The amino acidsequence obtained from micro-sequencing would be used to design a set ofdegenerate oligonucleotide probes to screen a cDNA library to identifythe gene encoding the putative receptor.

[0853] In another assay for antagonists, mammalian cells or a membranepreparation expressing the receptor would be incubated with labeled TATpolypeptide in the presence of the candidate compound. The ability ofthe compound to enhance or block this interaction could then bemeasured.

[0854] More specific examples of potential antagonists include anoligonucleotide that binds to the fusions of immunoglobulin with TATpolypeptide, and, in particular, antibodies including, withoutlimitation, poly- and monoclonal antibodies and antibody fragments,single-chain antibodies, anti-idiotypic antibodies, and chimeric orhumanized versions of such antibodies or fragments, as well as humanantibodies and antibody fragments. Alternatively, a potential antagonistmay be a closely related protein, for example, a mutated form of the TATpolypeptide that recognizes the receptor but imparts no effect, therebycompetitively inhibiting the action of the TAT polypeptide.

[0855] Another potential TAT polypeptide antagonist is an antisense RNAor DNA construct prepared using antisense technology, where, e.g., anantisense RNA or DNA molecule acts to block directly the translation ofmRNA by hybridizing to targeted mRNA and preventing protein translation.Antisense technology can be used to control gene expression throughtriple-helix formation or antisense DNA or RNA, both of which methodsare based on binding of a polynucleotide to DNA or RNA. For example, the5′ coding portion of the polynucleotide sequence, which encodes themature TAT polypeptides herein, is used to design an antisense RNAoligonucleotide of from about 10 to 40 base pairs in length. A DNAoligonucleotide is designed to be complementary to a region of the geneinvolved in transcription (triple helix—see Lee et al., Nucl. AcidsRes., 6:3073 (1979); Cooney et al., Science, 241: 456 (1988); Dervan etal., Science, 251:1360 (1991)), thereby preventing transcription and theproduction of the TAT polypeptide. The antisense RNA oligonucleotidehybridizes to the mRNA in vivo and blocks translation of the mRNAmolecule into the TAT polypeptide (antisense—Okano, Neurochem., 56:560(1991); Oligodeoxynucleotides as Antisense Inhibitors of Gene Expression(CRC Press: Boca Raton, Fla., 1988). The oligonucleotides describedabove can also be delivered to cells such that the antisense RNA or DNAmay be expressed in vivo to inhibit production of the TAT polypeptide.When antisense DNA is used, oligodeoxyribonucleotides derived from thetranslation-initiation site, e.g., between about −10 and +10 positionsof the target gene nucleotide sequence, are preferred.

[0856] Potential antagonists include small molecules that bind to theactive site, the receptor binding site, or growth factor or otherrelevant binding site of the TAT polypeptide, thereby blocking thenormal biological activity of the TAT polypeptide. Examples of smallmolecules include, but are not limited to, small peptides orpeptide-like molecules, preferably soluble peptides, and syntheticnon-peptidyl organic or inorganic compounds.

[0857] Ribozymes are enzymatic RNA molecules capable of catalyzing thespecific cleavage of RNA. Ribozymes act by sequence-specifichybridization to the complementary target RNA, followed byendonucleolytic cleavage. Specific ribozyme cleavage sites within apotential RNA target can be identified by known techniques. For furtherdetails see, e.g., Rossi, Current Biology, 4:469-471 (1994), and PCTpublication No. WO 97/33551 (published Sep. 18, 1997).

[0858] Nucleic acid molecules in triple-helix formation used to inhibittranscription should be single-stranded and composed ofdeoxynucleotides. The base composition of these oligonucleotides isdesigned such that it promotes triple-helix formation via Hoogsteenbase-pairing rules, which generally require sizeable stretches ofpurines or pyrimidines on one strand of a duplex. For further detailssee, e.g., PCT publication No. WO 97/33551, supra.

[0859] These small molecules can be identified by any one or more of thescreening assays discussed hereinabove and/or by any other screeningtechniques well known for those skilled in the art.

[0860] Isolated TAT polypeptide-encoding nucleic acid can be used hereinfor recombinantly producing TAT polypeptide using techniques well knownin the art and as described herein. In turn, the produced TATpolypeptides can be employed for generating anti-TAT antibodies usingtechniques well known in the art and as described herein.

[0861] Antibodies specifically binding a TAT polypeptide identifiedherein, as well as other molecules identified by the screening assaysdisclosed hereinbefore, can be administered for the treatment of variousdisorders, including cancer, in the form of pharmaceutical compositions.

[0862] If the TAT polypeptide is intracellular and whole antibodies areused as inhibitors, internalizing antibodies are preferred. However,lipofections or liposomes can also be used to deliver the antibody, oran antibody fragment, into cells. Where antibody fragments are used, thesmallest inhibitory fragment that specifically binds to the bindingdomain of the target protein is preferred. For example, based upon thevariable-region sequences of an antibody, peptide molecules can bedesigned that retain the ability to bind the target protein sequence.Such peptides can be synthesized chemically and/or produced byrecombinant DNA technology. See, e.g., Marasco et al, Proc. Natl. Acad.Sci. USA, 90: 7889-7893 (1993).

[0863] The formulation herein may also contain more than one activecompound as necessary for the particular indication being treated,preferably those with complementary activities that do not adverselyaffect each other. Alternatively, or in addition, the composition maycomprise an agent that enhances its function, such as, for example, acytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitoryagent. Such molecules are suitably present in combination in amountsthat are effective for the purpose intended.

[0864] The following examples are offered for illustrative purposesonly, and are not intended to limit the scope of the present inventionin any way.

[0865] All patent and literature references cited in the presentspecification are hereby incorporated by reference in their entirety.

EXAMPLES

[0866] Commercially available reagents referred to in the examples wereused according to manufacturer's instructions unless otherwiseindicated. The source of those cells identified in the followingexamples, and throughout the specification, by ATCC accession numbers isthe American Type Culture Collection, Manassas, Va.

EXAMPLE 1 Tissue Expression Profiling Using GeneExpress®

[0867] A proprietary database containing gene expression information(GeneExpress®, Gene Logic Inc., Gaithersburg, Md.) was analyzed in anattempt to identify polypeptides (and their encoding nucleic acids)whose expression is significantly upregulated in a particular tumortissue(s) of interest as compared to other tumor(s) and/or normaltissues. Specifically, analysis of the GeneExpress® database wasconducted using either software available through Gene Logic Inc.,Gaithersburg, Md., for use with the GeneExpress® database or withproprietary software written and developed at Genentech, Inc. for usewith the GeneExpress® database. The rating of positive hits in theanalysis is based upon several criteria including, for example, tissuespecificity, tumor specificity and expression level in normal essentialand/or normal proliferating tissues. The following is a list ofmolecules whose tissue expression profile as determined from an analysisof the GeneExpress® database evidences high tissue expression andsignificant upregulation of expression in a specific tumor or tumors ascompared to other tumor(s) and/or normal tissues and optionallyrelatively low expression in normal essential and/or normalproliferating tissues. As such, the molecules listed below are excellentpolypeptide targets for the diagnosis and therapy of cancer in mammals.upregulation of Molecule expression in: as compared to: DNA96792(TAT239) colon tumor normal colon tissue DNA96792 (TAT239) rectum tumornormal rectum tissue DNA96792 (TAT239) pancreas tumor normal pancreastissue DNA96792 (TAT239) lung tumor normal lung tissue DNA96792 (TAT239)stomach tumor normal stomach tissue DNA96792 (TAT239) esophagus tumornormal esophagus tissue DNA96792 (TAT239) breast tumor normal breasttissue DNA96792 (TAT239) uterus tumor normal uterus tissue DNA225793(TAT223) ovarian tumor normal ovarian tissue DNA225793 (TAT223) kidneytumor normal kidney tissue DNA227611 (TAT175) prostate tumor normalprostate tissue DNA227611 (TAT175) colon tumor normal colon tissueDNA227611 (TAT175) breast tumor normal breast tissue DNA261021 (TAT208)breast tumor normal breast tissue DNA260655 (TAT209) lung tumor normallung tissue DNA260655 (TAT209) colon tumor normal colon tissue DNA260655(TAT209) breast tumor normal breast tissue DNA260655 (TAT209) livertumor normal liver tissue DNA260655 (TAT209) ovarian tumor normalovarian tissue DNA260655 (TAT209) skin tumor normal skin tissueDNA260655 (TAT209) spleen tumor normal spleen tissue DNA260655 (TAT209)myeloid tumor normal myeloid tissue DNA260655 (TAT209) muscle tumornormal muscle tissue DNA260655 (TAT209) bone tumor normal bone tissueDNA261001 (TAT181) bone tumor normal bone tissue DNA261001 (TAT181) lungtumor normal lung tissue DNA266928 (TAT182) bone tumor normal bonetissue DNA266928 (TAT182) lung tumor normal lung tissue DNA268035(TAT222) breast tumor normal breast tissue DNA268035 (TAT222) colontumor normal colon tissue DNA268035 (TAT222) ovarian tumor normalovarian tissue DNA268035 (TAT222) uterine tumor normal uterine tissueDNA77509 (TAT177) colon tumor normal colon tissue DNA87993 (TAT235)breast tumor normal breast tissue DNA87993 (TAT235) pancreatic tumornormal pancreatic tissue DNA87993 (TAT235) lung tumor normal lung tissueDNA87993 (TAT235) colon tumor normal colon tissue DNA87993 (TAT235)rectum tumor normal rectum tissue DNA87993 (TAT235) gallbladder tumornormal gallbladder tissue DNA92980 (TAT234) bone tumor normal bonetissue DNA92980 (TAT234) breast tumor normal breast tissue DNA92980(TAT234) cervical tumor normal cervical tissue DNA92980 (TAT234) colontumor normal colon tissue DNA92980 (TAT234) rectum tumor normal rectumtissue DNA92980 (TAT234) endometrial tumor normal endometrial tissueDNA92980 (TAT234) liver tumor normal liver tissue DNA92980 (TAT234) lungtumor normal lung tissue DNA92980 (TAT234) ovarian tumor normal ovariantissue DNA92980 (TAT234) pancreatic tumor normal pancreatic tissueDNA92980 (TAT234) skin tumor normal skin tissue DNA92980 (TAT234) softtissue tumor normal soft tissue DNA92980 (TAT234) stomach tumor normalstomach tissue DNA92980 (TAT234) bladder tumor normal bladder tissueDNA92980 (TAT234) thyroid tumor normal thyroid tissue DNA105792 (TAT233)bone tumor normal bone tissue DNA105792 (TAT233) breast tumor normalbreast tissue DNA105792 (TAT233) endometrial tumor normal endometrialtissue DNA105792 (TAT233) esophagus tumor normal esophagus tissueDNA105792 (TAT233) kidney tumor normal kidney tissue DNA105792 (TAT233)lung tumor normal lung tissue DNA105792 (TAT233) ovarian tumor normalovarian tissue DNA105792 (TAT233) pancreatic tumor normal pancreatictissue DNA105792 (TAT233) prostate tumor normal prostate tissueDNA105792 (TAT233) soft tissue tumor normal soft tissue DNA105792(TAT233) stomach tumor normal stomach tissue DNA105792 (TAT233) thyroidtumor normal thyroid tissue DNA105792 (TAT233) bladder tumor normalbladder tissue DNA105792 (TAT233) brain tumor normal brain tissueDNA105792 (TAT233) Wilm's tumor normal associated tissue DNA119474(TAT228) uterine tumor normal uterine tissue DNA119474 (TAT228) ovariantumor normal ovarian tissue DNA280351 (TAT248) squamous cell normalsquamous cell lung lung tumor tissue DNA280351 (TAT248) colon tumornormal colon tissue DNA150648 (TAT232) liver tumor normal liver tissueDNA150648 (TAT232) breast tumor normal breast tissue DNA150648 (TAT232)brain tumor normal brain tissue DNA150648 (TAT232) lung tumor normallung tissue DNA150648 (TAT232) colon tumor normal colon tissue DNA150648(TAT232) rectum tumor normal rectum tissue DNA150648 (TAT232) kidneytumor normal kidney tissue DNA150648 (TAT232) bladder tumor normalbladder tissue DNA179651 (TAT224) breast tumor normal breast tissueDNA179651 (TAT224) cervical tumor normal cervical tissue DNA179651(TAT224) colon tumor normal colon tissue DNA179651 (TAT224) rectum tumornormal rectum tissue DNA179651 (TAT224) uterine tumor normal uterinetissue DNA179651 (TAT224) lung tumor normal lung tissue DNA179651(TAT224) ovarian tumor normal ovarian tissue DNA207698 (TAT237) breasttumor normal breast tissue DNA207698 (TAT237) colon tumor normal colontissue DNA207698 (TAT237) ovarian tumor normal ovarian tissue DNA207698(TAT237) pancreatic tumor normal pancreatic tissue DNA207698 (TAT237)stomach tumor normal stomach tissue DNA225886 (TAT236) breast tumornormal breast tissue DNA225886 (TAT236) colon tumor normal colon tissueDNA225886 (TAT236) rectum tumor normal rectum tissue DNA225886 (TAT236)endometrial tumor normal endometrial tissue DNA225886 (TAT236) lungtumor normal lung tissue DNA225886 (TAT236) ovarian tumor normal ovariantissue DNA225886 (TAT236) pancreas tumor normal pancreas tissueDNA225886 (TAT236) prostate tumor normal prostate tissue DNA225886(TAT236) bladder tumor normal bladder tissue DNA226717 (TAT185) gliomanormal glial tissue DNA226717 (TAT185) brain tumor normal brain tissueDNA227162 (TAT225) breast tumor normal breast tissue DNA227162 (TAT225)endometrial tumor normal endometrial tissue DNA227162 (TAT225) lungtumor normal lung tissue DNA227162 (TAT225) ovarian tumor normal ovariantissue DNA277804 (TAT247) breast tumor normal breast tissue DNA277804(TAT247) endometrial tumor normal endometrial tissue DNA277804 (TAT247)lung tumor normal lung tissue DNA277804 (TAT247) ovarian tumor normalovarian tissue DNA233034 (TAT174) glioma normal glial tissue DNA233034(TAT174) brain tumor normal brain tissue DNA266920 (TAT214) gliomanormal glial tissue DNA266920 (TAT214) brain tumor normal brain tissueDNA266921 (TAT220) glioma normal glial tissue DNA266921 (TAT220) braintumor normal brain tissue DNA266922 (TAT221) glioma normal glial tissueDNA266922 (TAT221) brain tumor normal brain tissue DNA234441 (TAT201)colon tumor normal colon tissue DNA234441 (TAT201) rectum tumor normalrectum tissue DNA234834 (TAT179) breast tumor normal breast tissueDNA234834 (TAT179) colon tumor normal colon tissue DNA234834 (TAT179)rectum tumor normal rectum tissue DNA234834 (TAT179) prostate tumornormal prostate tissue DNA234834 (TAT179) pancreatic tumor normalpancreatic tissue DNA234834 (TAT179) endometrial tumor normalendometrial tissue DNA234834 (TAT179) lung tumor normal lung tissueDNA234834 (TAT179) ovarian tumor normal ovarian tissue DNA247587(TAT216) breast tumor normal breast tissue DNA247587 (TAT216) lung tumornormal lung tissue DNA247587 (TAT216) ovarian tumor normal ovariantissue DNA247587 (TAT216) pancreatic tumor normal pancreatic tissueDNA247587 (TAT216) stomach tumor normal stomach tissue DNA247587(TAT216) urinary tumor normal urinary tissue DNA255987 (TAT218) breasttumor normal breast tissue DNA56041 (TAT206) lymphoid tumor normallymphoid tissue DNA257845 (TAT374) lymphoid tumor normal lymphoid tissueDNA247476 (TAT180) bone tumor normal bone tissue DNA247476 (TAT180)breast tumor normal breast tissue DNA247476 (TAT180) colon tumor normalcolon tissue DNA247476 (TAT180) rectum tumor normal rectum tissueDNA247476 (TAT180) kidney tumor normal kidney tissue DNA247476 (TAT180)lung tumor normal lung tissue DNA247476 (TAT180) pancreatic tumor normalpancreatic tissue DNA247476 (TAT180) prostate tumor normal prostatetissue DNA247476 (TAT180) skin tumor normal skin tissue DNA247476(TAT180) soft tissue tumor normal soft tissue DNA247476 (TAT180) stomachtumor normal stomach tissue DNA260990 (TAT375) bone tumor normal bonetissue DNA260990 (TAT375) breast tumor normal breast tissue DNA260990(TAT375) colon tumor normal colon tissue DNA260990 (TAT375) rectum tumornormal rectum tissue DNA260990 (TAT375) kidney tumor normal kidneytissue DNA260990 (TAT375) lung tumor normal lung tissue DNA260990(TAT375) pancreatic tumor normal pancreatic tissue DNA260990 (TAT375)prostate tumor normal prostate tissue DNA260990 (TAT375) skin tumornormal skin tissue DNA260990 (TAT375) soft tissue tumor normal softtissue DNA260990 (TAT375) stomach tumor normal stomach tissue DNA261013(TAT176) breast tumor normal breast tissue DNA261O13 (TAT176) colontumor normal colon tissue DNA261013 (TAT176) rectum tumor normal rectumtissue DNA261013 (TAT176) lung tumor normal lung tissue DNA261013(TAT176) ovarian tumor normal ovarian tissue DNA261013 (TAT176) stomachtumor normal stomach tissue DNA262144 (TAT184) breast tumor normalbreast tissue DNA262144 (TAT184) colon tumor normal colon tissueDNA262l44 (TAT184) rectum tumor normal rectum tissue DNA262l44 (TAT184)endometrial tumor normal endometrial tissue DNA262l44 (TAT184) kidneytumor normal kidney tissue DNA262144 (TAT184) lung tumor normal lungtissue DNA262144 (TAT184) ovarian tumor normal ovarian tissue DNA267342(TAT213)) stroma associated normal associated tissues, with thefollowing respectively tumors: bone, breast, colon, rectum, lung,ovarian, pancreas, soft tissue, bladder DNA267626 (TAT217) breast tumornormal breast tissue DNA267626 (TAT217) colon tumor normal colon tissueDNA267626 (TAT217) rectum tumor normal rectum tissue DNA267626 (TAT217)endometrial tumor normal endometrial tissue DNA267626 (TAT217) lungtumor normal lung tissue DNA267626 (TAT217) pancreatic tumor normalpancreatic tissue DNA268334 (TAT202) kidney tumor normal kidney tissueDNA269238 (TAT215) kidney tumor normal kidney tissue DNA272578 (TAT238)liver tumor normal liver tissue DNA272578 (TAT238) lung tumor normallung tissue DNA272578 (TAT238) ovarian tumor normal ovarian tissueDNA304853 (TAT376) breast tumor normal breast tissue DNA304853 (TAT376)colon tumor normal colon tissue DNA304853 (TAT376) rectum tumor normalrectum tissue DNA304853 (TAT376) prostate tumor normal prostate tissueDNA304853 (TAT376) pancreatic tumor normal pancreatic tissue DNA304853(TAT376) endometrial tumor normal endometrial tissue DNA304853 (TAT376)lung tumor normal lung tissue DNA304853 (TAT376) ovarian tumor normalovarian tissue DNA304854 (TAT377) breast tumor normal breast tissueDNA304854 (TAT377) colon tumor normal colon tissue DNA304854 (TAT377)rectum tumor normal rectum tissue DNA304854 (TAT377) prostate tumornormal prostate tissue DNA304854 (TAT377) pancreatic tumor normalpancreatic tissue DNA304854 (TAT377) endometrial tumor normalendometrial tissue DNA304854 (TAT377) lung tumor normal lung tissueDNA304854 (TAT377) ovarian tumor normal ovarian tissue DNA304855(TAT378) breast tumor normal breast tissue DNA304855 (TAT378) colontumor normal colon tissue DNA304855 (TAT378) rectum tumor normal rectumtissue DNA304855 (TAT378) prostate tumor normal prostate tissueDNA304855 (TAT378) pancreatic tumor normal pancreatic tissue DNA304855(TAT378) endometrial tumor normal endometrial tissue DNA304855 (TAT378)lung tumor normal lung tissue DNA304855 (TAT378) ovarian tumor normalovarian tissue DNA287971 (TAT379) bone tumor normal bone tissueDNA287971 (TAT379) breast tumor normal breast tissue DNA287971 (TAT379)colon tumor normal colon tissue DNA287971 (TAT379) rectum tumor normalrectum tissue DNA287971 (TAT379) kidney tumor normal kidney tissueDNA287971 (TAT379) lung tumor normal lung tissue DNA287971 (TAT379)pancreatic tumor normal pancreatic tissue DNA287971 (TAT379) prostatetumor normal prostate tissue DNA287971 (TAT379) skin tumor normal skintissue DNA287971 (TAT379) soft tissue tumor normal soft tissue DNA287971(TAT379) stomach tumor normal stomach tissue

EXAMPLE 2 Microarray Analysis to Detect Upregulation of TAT Polypeptidesin Cancerous Tumors

[0868] Nucleic acid microarrays, often containing thousands of genesequences, are useful for identifying differentially expressed genes indiseased tissues as compared to their normal counterparts. Using nucleicacid microarrays, test and control mRNA samples from test and controltissue samples are reverse transcribed and labeled to generate cDNAprobes. The cDNA probes are then hybridized to an array of nucleic acidsimmobilized on a solid support. The array is configured such that thesequence and position of each member of the array is known. For example,a selection of genes known to be expressed in certain disease states maybe arrayed on a solid support. Hybridization of a labeled probe with aparticular array member indicates that the sample from which the probewas derived expresses that gene. If the hybridization signal of a probefrom a test (disease tissue) sample is greater than hybridization signalof a probe from a control (normal tissue) sample, the gene or genesoverexpressed in the disease tissue are identified. The implication ofthis result is that an overexpressed protein in a diseased tissue isuseful not only as a diagnostic marker for the presence of the diseasecondition, but also as a therapeutic target for treatment of the diseasecondition.

[0869] The methodology of hybridization of nucleic acids and microarraytechnology is well known in the art. In one example, the specificpreparation of nucleic acids for hybridization and probes, slides, andhybridization conditions are all detailed in PCT patent application Ser.No. PCT/US01/10482, filed on Mar. 30, 2001 and which is hereinincorporated by reference.

[0870] In the present example, cancerous tumors derived from varioushuman tissues were studied for upregulated gene expression relative tocancerous tumors from different tissue types and/or non-cancerous humantissues in an attempt to identify those polypeptides which areoverexpressed in a particular cancerous tumor(s). In certainexperiments, cancerous human tumor tissue and non-cancerous human tumortissue of the same tissue type (often from the same patient) wereobtained and analyzed for TAT polypeptide expression. Additionally,cancerous human tumor tissue from any of a variety of different humantumors was obtained and compared to a “universal” epithelial controlsample which was prepared by pooling non-cancerous human tissues ofepithelial origin, including liver, kidney, and lung. mRNA isolated fromthe pooled tissues represents a mixture of expressed gene products fromthese different tissues. Microarray hybridization experiments using thepooled control samples generated a linear plot in a 2-color analysis.The slope of the line generated in a 2-color analysis was then used tonormalize the ratios of (test:control detection) within each experiment.The normalized ratios from various experiments were then compared andused to identify clustering of gene expression. Thus, the pooled“universal control” sample not only allowed effective relative geneexpression determinations in a simple 2-sample comparison, it alsoallowed multi-sample comparisons across several experiments.

[0871] In the present experiments, nucleic acid probes derived from theherein described TAT polypeptide-encoding nucleic acid sequences wereused in the creation of the microarray and RNA from various tumortissues were used for the hybridization thereto. Below is shown theresults of these experiments, demonstrating that various TATpolypeptides of the present invention are significantly overexpressed invarious human tumor tissues as compared to their normal counterparttissue(s). Moreover, all of the molecules shown below are significantlyoverexpressed in their specific tumor tissue(s) as compared to in the“universal” epithelial control. As described above, these datademonstrate that the TAT polypeptides of the present invention areuseful not only as diagnostic markers for the presence of one or morecancerous tumors, but also serve as therapeutic targets for thetreatment of those tumors. upregulation of Molecule expression in: ascompared to: DNA172500 (TAT219) renal cell carcinoma normal kidney(renal cell) tissue

EXAMPLE 3 Quantitative Analysis of TAT mRNA Expression

[0872] In this assay, a 5′ nuclease assay (for example, TaqMan®) andreal-time quantitative PCR (for example, ABI Prizm 7700 SequenceDetection System® (Perkin Elmer, Applied Biosystems Division, FosterCity, Calif.)), were used to find genes that are significantlyoverexpressed in a cancerous tumor or tumors as compared to othercancerous tumors or normal non-cancerous tissue. The 5′ nuclease assayreaction is a fluorescent PCR-based technique which makes use of the 5′exonuclease activity of Taq DNA polymerase enzyme to monitor geneexpression in real time. Two oligonucleotide primers (whose sequencesare based upon the gene or EST sequence of interest) are used togenerate an amplicon typical of a PCR reaction. A third oligonucleotide,or probe, is designed to detect nucleotide sequence located between thetwo PCR primers. The probe is non-extendible by Taq DNA polymeraseenzyme, and is labeled with a reporter fluorescent dye and a quencherfluorescent dye. Any laser-induced emission from the reporter dye isquenched by the quenching dye when the two dyes are located closetogether as they are on the probe. During the PCR amplificationreaction, the Taq DNA polymerase enzyme cleaves the probe in atemplate-dependent manner. The resultant probe fragments disassociate insolution, and signal from the released reporter dye is free from thequenching effect of the second fluorophore. One molecule of reporter dyeis liberated for each new molecule synthesized, and detection of theunquenched reporter dye provides the basis for quantitativeinterpretation of the data.

[0873] The 5′ nuclease procedure is run on a real-time quantitative PCRdevice such as the ABI Prism 7700™ Sequence Detection. The systemconsists of a thermocycler, laser, charge-coupled device (CCD) cameraand computer. The system amplifies samples in a 96-well format on athermocycler. During amplification, laser-induced fluorescent signal iscollected in real-time through fiber optics cables for all 96 wells, anddetected at the CCD. The system includes software for running theinstrument and for analyzing the data.

[0874] The starting material for the screen was mRNA isolated from avariety of different cancerous tissues. The mRNA is quantitatedprecisely, e.g., fluorometrically. As a negative control, RNA wasisolated from various normal tissues of the same tissue type as thecancerous tissues being tested.

[0875] 5′ nuclease assay data are initially expressed as Ct, or thethreshold cycle. This is defined as the cycle at which the reportersignal accumulates above the background level of fluorescence. The ΔCtvalues are used as quantitative measurement of the relative number ofstarting copies of a particular target sequence in a nucleic acid samplewhen comparing cancer mRNA results to normal human mRNA results. As oneCt unit corresponds to 1 PCR cycle or approximately a 2-fold relativeincrease relative to normal, two units corresponds to a 4-fold relativeincrease, 3 units corresponds to an 8-fold relative increase and so on,one can quantitatively measure the relative fold increase in mRNAexpression between two or more different tissues. Using this technique,the molecules listed below have been identified as being significantlyoverexpressed in a particular tumor(s) as compared to their normalnon-cancerous counterpart tissue(s) (from both the same and differenttissue donors) and thus, represent excellent polypeptide targets for thediagnosis and therapy of cancer in mammals. upregulation of Moleculeexpression in: as compared to: DNA261021 (TAT208) lung tumor normal lungtissue DNA77509 (TAT177) colon tumor normal colon tissue DNA119474(TAT226) ovarian tumor normal ovarian tissue DNA179651 (TAT224) ovariantumor normal ovarian tissue DNA226717 (TAT185) glioma normal glial/braintissue DNA227162 (TAT225) ovarian tumor normal ovarian tissue DNA277804(TAT247) ovarian tumor normal ovarian tissue DNA233034 (TAT174) gliomanormal glial/brain tissue DNA266920 (TAT214) glioma normal glial/braintissue DNA266921 (TAT220) glioma normal glial/brain tissue DNA266922(TAT221) glioma normal glial/brain tissue DNA234441 (TAT201) colon tumornormal colon tissue DNA234834 (TAT179) colon tumor normal colon tissueDNA247587 (TAT216) squamous cell normal squamous cell lung lung tumortissue DNA255987 (TAT218) breast tumor normal breast tissue DNA247476(TAT180) colon tumor normal colon tissue DNA260990 (TAT375) colon tumornormal colon tissue DNA261013 (TAT176) breast tumor normal breast tissueDNA262144 (TAT184) kidney tumor normal kidney tissue DNA267342 (TAT213)breast tumor normal breast tissue DNA267626 (TAT217) breast tumor normalbreast tissue DNA268334 (TAT202) kidney tumor normal kidney tissueDNA269238 (TAT215) kidney tumor normal kidney tissue DNA87993 (TAT235)lung tumor normal lung tissue DNA92980 (TAT234) ovarian tumor normalovarian tissue DNA105792 (TAT233) lung tumor normal lung tissueDNA207698 (TAT237) colon tumor normal colon tissue DNA225886 (TAT236)colon tumor normal colon tissue DNA272578 (TAT238) ovarian tumor normalovarian tissue DNA304853 (TAT376) colon tumor normal colon tissueDNA304854 (TAT377) colon tumor normal colon tissue DNA304855 (TAT378)colon tumor normal colon tissue DNA287971 (TAT379) colon tumor normalcolon tissue

EXAMPLE 4 In Situ Hybridization

[0876] In situ hybridization is a powerful and versatile technique forthe detection and localization of nucleic acid sequences within cell ortissue preparations. It may be useful, for example, to identify sites ofgene expression, analyze the tissue distribution of transcription,identify and localize viral infection, follow changes in specific mRNAsynthesis and aid in chromosome mapping.

[0877] In situ hybridization was performed following an optimizedversion of the protocol by Lu and Gillett, Cell Vision 1:169-176 (1994),using PCR-generated ³³P-labeled riboprobes. Briefly, formalin-fixed,paraffin-embedded human tissues were sectioned, deparaffinized,deproteinated in proteinase K (20 g/ml) for 15 minutes at 37° C., andfurther processed for in situ hybridization as described by Lu andGillett, supra. A [³³−P]UTP-labeled antisense riboprobe was generatedfrom a PCR product and hybridized at 55° C. overnight. The slides weredipped in Kodak NTB2 nuclear track emulsion and exposed for 4 weeks.

[0878]³³P-Riboprobe Synthesis

[0879] 6.0 μl (125 mCi) of ³³P-UTP (Amersham BF 1002, SA<2000 Ci/mmol)were speed vac dried. To each tube containing dried ³³P-UTP, thefollowing ingredients were added:

[0880] 2.0 μl 5× transcription buffer

[0881] 1.0 μl DTT (100 mM)

[0882] 2.0 μl NTP mix (2.5 mM: 10 μ; each of 10 mM GTP, CTP & ATP+10 μlH₂O)

[0883] 1.0 μl UTP (50 μM)

[0884] 1.0 μl Rnasin

[0885] 1.0 μl DNA template (1 μg)

[0886] 1.0 μl H₂O

[0887] 1.0 μl RNA polymerase (for PCR products T3=AS, T7=S, usually)

[0888] The tubes were incubated at 37° C. for one hour. 1.0 μl RQ1 DNasewere added, followed by incubation at 37° C. for 15 minutes. 90 μl TE(10 mM Tris pH 7.6/1 mM EDTA pH 8.0) were added, and the mixture waspipetted onto DE81 paper. The remaining solution was loaded in aMicrocon-50 ultrafiltration unit, and spun using program 10 (6 minutes).The filtration unit was inverted over a second tube and spun usingprogram 2 (3 minutes). After the final recovery spin, 100 μl TE wereadded. 1 μl of the final product was pipetted on DE81 paper and countedin 6 ml of Biofluor II.

[0889] The probe was run on a TBE/urea gel. 1-3 μl of the probe or 5 μlof RNA Mrk III were added to 3 μl of loading buffer. After heating on a95° C. heat block for three minutes, the probe was immediately placed onice. The wells of gel were flushed, the sample loaded, and run at180-250 volts for 45 minutes. The gel was wrapped in saran wrap andexposed to XAR film with an intensifying screen in −70° C. freezer onehour to overnight.

[0890]³³P-Hybridization

[0891] A. Pretreatment of Frozen Sections

[0892] The slides were removed from the freezer, placed on aluminiumtrays and thawed at room temperature for 5 minutes. The trays wereplaced in 55° C. incubator for five minutes to reduce condensation. Theslides were fixed for 10 minutes in 4% paraformaldehyde on ice in thefume hood, and washed in 0.5×SSC for 5 minutes, at room temperature (25ml 20×SSC+975 ml SQ H₂O). After deproteination in 0.5 μg/ml proteinase Kfor 10 minutes at 37° C. (12.5 μl of 10 mg/ml stock in 250 ml prewarmedRNase-free RNAse buffer), the sections were washed in 0.5×SSC for 10minutes at room temperature. The sections were dehydrated in 70%, 95%,100% ethanol, 2 minutes each.

[0893] B. Pretreatment of Paraffin-Embedded Sections

[0894] The slides were deparaffinized, placed in SQ H₂O and rinsed twicein 2×SSC at room temperature, for 5 minutes each time. The sections weredeproteinated in 20 μg/ml proteinase K (500 μl of 10 mg/ml in 250 mlRNase-free RNase buffer; 37° C., 15 minutes)—human embryo, or8×proteinase K (100 μl in 250 ml Rnase buffer, 37° C., 30minutes)—formalin tissues. Subsequent rinsing in 0.5 x SSC anddehydration were performed as described above.

[0895] C. Prehybridization

[0896] The slides were laid out in a plastic box lined with Box buffer(4×SSC, 50% formamide)—saturated filter paper.

[0897] D. Hybridization

[0898] 1.0×10⁶ cpm probe and 1.0 μl tRNA (50 mg/ml stock) per slide wereheated at 95° C. for 3 minutes. The slides were cooled on ice, and 48 μlhybridization buffer were added per slide. After vortexing, 50 μl ³³Pmix were added to 50 μl prehybridization on slide. The slides wereincubated overnight at 55° C.

[0899] E. Washes

[0900] Washing was done 2×10 minutes with 2×SSC, EDTA at roomtemperature (400 ml 20×SSC+16 ml 0.25M EDTA, V=4 L), followed by RNaseAtreatment at 37° C. for 30 minutes (500 μl of 10 mg/ml in 250 ml Rnasebuffer=20 μg/ml), The slides were washed 2×10 minutes with 2×SSC, EDTAat room temperature. The stringency wash conditions were as follows: 2hours at 55° C., 0.1×SSC, EDTA (20 ml 20×SSC+16 ml EDTA, V_(f)=4 L).

[0901] F. Oligonucleotides

[0902] In situ analysis was performed on a variety of DNA sequencesdisclosed herein. The oligonucleotides employed for these analyses wereobtained so as to be complementary to the nucleic acids (or thecomplements thereof) as shown in the accompanying figures.

[0903] G. Results

[0904] In situ analysis was performed on a variety of DNA sequencesdisclosed herein. The results from these analyses are as follows.

[0905] (1) DNA119474 (TAT226)

[0906] Positive expression is observed in 2 of 3 non-small cell lungcarcinomsa, 2 of 3 pancreatic adenocarcinomas, 1 of 2 hepatocellularcarcinomas and 2 of 3 endometrial adenocarcinomas. In a separateanalysis, 10 of 16 ovarian adenocarcinomas are positive and 3 of 9endometrial adenocarcinomas are positive. All normal tissues examinedare negative for expression.

[0907] (2) DNA179651 (TAT224)

[0908] In one analysis, expression is seen in 5 of 7 uterineadenocarcinomas and in 7 of 16 ovarian adenocarcinomas. Two cases ofdysgerminoma are positive as is one case of a Brenner's tumor.

[0909] In another analysis, 33 of 68 ovarian adenocarcinomas (serous,mucinous, endometrioid, clear cell) are positive for expression.Moderate to strong expression is seen in normal endometrium (no othernormal tissues) and normal ovarian stroma is negative.

[0910] In yet another analysis, positive:expression is seen in 3/3endometrial, 2/2 colorectal, 1/3 transitional cell, 3/3 lung and 1/2ovarian cancers.

[0911] (3) DNA227162 (TAT225)

[0912] Expression is seen in the following tumors: 1 of 3 lung cancers,1 of 2 colon cancers, 1 of 1 pancreatic cancer, 2 of 3 transitional cellcarcinomas, 3 of 3 endometrial carcinomas, 2 of 2 ovarian carcinomas and2 of 3 malignant melanomas.

[0913] In a separate analysis, positive expression is seen in 6 of 9uterine adenocarcinomas and 6 of 14 ovarian tumors.

[0914] With regard to expression in normal tissues, weak expression isseen in one core of urothelium (superficial cell layer positive) and onecore of gall bladder mucosa. All other normal tissues are negative forexpression.

[0915] (4) DNA277804 (TAT247)

[0916] Expression is seen in the following tumors: 1 of 3 lung cancers,1 of 2 colon cancers, 1 of 1 pancreatic cancer, 2 of 3 transitional cellcarcinomas, 3 of 3 endometrial carcinomas, 2 of 2 ovarian carcinomas and2 of 3 malignant melanomas.

[0917] In a separate analysis, positive expression is seen in 6 of 9uterine adenocarcinomas and 6 of 14 ovarian tumors.

[0918] With regard to expression in normal tissues, weak expression isseen in one core of urothelium (superficial cell layer positive) and onecore of gall bladder mucosa. All other normal tissues are negative forexpression.

[0919] (5) DNA234441 (TAT201)

[0920] Weak (and inconsistent) expression is seen in normal kidney,normal colon mucosa and normal gallbladder. Weak to moderate, thoughsomewhat inconsistent expression is seen in normal gastrointestinalmucosa (esophagus, stomach, small intestine, colon, anus). Significantexpression in tumors is seen as follows: 11 of 12 colorectaladenocarcinomas, 4 of 4 gastric adenocarcinomas, 6 of 8 metastaticadenocarcinomas, 4 of 4 esophageal cancers and 1 of 2 pancreaticadenocarcinomas.

[0921] (6) DNA234834 (TAT179)

[0922] With regard to normal tissues, it appears that there is a weaksignal in colon mucosa and breast epithelium. With regard to tumortissues, expression is seen in 1 of 2 non-small cell lung carcinomas, 2of 2 colon cancers, 1 of 2 pancreatic cancers, 1 of 2 hepatocellularcarcinomas, 3 of 3 endometrial carcinomas, 1 of 2 ovarian carcinomas and2 of 3 malignant melanomas.

[0923] In a separate analysis, 12 of 16 colorectal carcinomas arepositive for expression; 2 of 8 gastric adenocarcinoma are positive forexpression, 2 of 4 esophageal carcinomas are positive for expression; 7of 10 metastatic adenocarcinoma are positive for expression and 1 of 2cholangiocarcinomas are positive for expression. Expression level istumor tissues is consistently higher than in normal tissues.

[0924] (7) DNA247587 (TAT216)

[0925] Expression is seen in 13 of 16 non-small cell lung carcinomas.Expression is also seen in benign bronchial mucosa and occasionalactivated pneumocytes. Moreover, 65 of 89 cases of invasive breastcancer are positive for expression. Strong expression is seen in normalskin and normal urothelium. Moderate expression is seen in normalmammary epithelium and trophoblasts of the placenta, weak expression innormal prostate and normal gall bladder epithelium and distal renaltubules.

[0926] (8) DNA56041 (TAT206)

[0927] In non-malignant lymphoid tissue expression is seen in occasionallarger lymphoid cells within germinal centers and in interfollicularregions. Positive cells account for less than 5% of all lymphoid cells.In section of spleen scattered positive cells are seen within theperiarteriolar lymphoid sheath and in the marginal zone.

[0928] In four cases of Hodgkin's disease Reed-Sternberg cells arenegative, positive signal is observed in scattered lymphocytes. Three offour cases of follicular lymphoma are positive (weak to moderate), fourof six cases of diffuse large cell lymphoma are positive (weak tomoderate). Two cases of small lymphocytic lymphoma show a weak signal invariable proportion of cells.

[0929] (9) DNA257845 (TAT374)

[0930] In non-malignant lymphoid tissue expression is seen in occasionallarger lymphoid cells within germinal centers and in interfollicularregions. Positive cells account for less than 5% of all lymphoid cells.In section of spleen scattered positive cells are seen within theperiarteriolar lymphoid sheath and in the marginal zone.

[0931] In four cases of Hodgkin's disease Reed-Sternberg cells arenegative, positive signal is observed in scattered lymphocytes. Three offour cases of follicular lymphoma are positive (weak to moderate), fourof six cases of diffuse large cell lymphoma are positive (weak tomoderate). Two cases of small lymphocytic lymphoma show a weak signal invariable proportion of cells.

[0932] (10) DNA247476 (TAT180)

[0933] With regard to normal tissues, strong expression is seen inprostatic epithelium and in a section of peripheral nerve. Moderateexpression is seen in renal glomeruli. Weak expression is seen in bileduct epithelium and mammary epithelium. Two sections of stomach showweak expression in a subset of gastric glands. Sections of colon andsmall intestine show a signal in lamina propria and/or submucosa, mostlikely in small autonomic nerve fibers. Another independent ISH studyfails to show expression in peripheral nerves of prostatectomy sections,despite adequate signal in prostatic epithelium.

[0934] In a separate analysis, 42 of 77 breast tumors are positive (55%)for expression.

[0935] In yet another analysis, 8 of 11 breast cancers are positive forexpression.

[0936] In yet another analysis, expression is seen in 1/2 non-small celllung carcinomas, 1/3 colorectal adenocarcinomas, 2/3 pancreaticadenocarcinomas, 1/1 prostate cancers, 1/3 transitional cell carcinomas,3/3 renal cell carcinomas, 3/3 endometrial adenocarcinomas, 1/2 ovarianadenocarcinomas and 1/3 malignant melanomas.

[0937] In yet another analysis, expression is seen in 42 of 45 (93%)prostate cancers.

[0938] In yet another analysis, expression is seen in all of 23 primaryand in 12 of 15 (80%) metastatic prostate cancers analyzed.

[0939] In yet another analysis, expression is observed in the followingcarcinomas as follows: pancreatic adenocarcinoma—2 of 2 cases arepositive; colorectal adenocarcinoma—12 of 14 cases are positive; gastricadenocarcinoma—6 of 8 cases are positive; esophageal carcinoma—2 of 3cases are positive; cholangiocarcinoma —1 of 1 case is positive;metastatic adenocarcinoma (ovary, liver, lymph node, diaphragm)—8 of 12cases are positive.

[0940] (11) DNA260990 (TAT375)

[0941] With regard to normal tissues, strong expression is seen inprostatic epithelium and in a section of peripheral nerve. Moderateexpression is seen in renal glomeruli. Weak expression is seen in bileduct epithelium and mammary epithelium. Two sections of stomach showweak expression in a subset of gastric glands. Sections of colon andsmall intestine show a signal in lamina propria and/or submucosa, mostlikely in small autonomic nerve fibers. Another independent ISH studyfails to show expression in peripheral nerves of prostatectomy sections,despite adequate signal in prostatic epithelium.

[0942] In a separate analysis, 42 of 77 breast tumors are positive (55%)for expression.

[0943] In yet another analysis, 8 of 11 breast cancers are positive forexpression.

[0944] In yet another analysis, expression is seen in 1/2 non-small celllung carcinomas, 1/3 colorectal adenocarcinomas, 2/3 pancreaticadenocarcinomas, 1/1 prostate cancers, 1/3 transitional cell carcinomas,3/3 renal cell carcinomas, 3/3 endometrial adenocarcinomas, 1/2 ovarianadenocarcinomas and 1/3 malignant melanomas.

[0945] In yet another analysis, expression is seen in 42 of 45 (93%)prostate cancers.

[0946] In yet another analysis, expression is seen in all of 23 primaryand in 12 of 15 (80%) metastatic prostate cancers analyzed.

[0947] In yet another analysis, expression is observed in the followingcarcinomas as follows: pancreatic adenocarcinoma—2 of 2 cases arepositive; colorectal adenocarcinoma—12 of 14 cases are positive; gastricadenocarcinoma—6 of 8 cases are positive; esophageal carcinoma—2 of 3cases are positive; cholangiocarcinoma —1 of 1 case is positive;metastatic adenocarcinoma (ovary, liver, lymph node, diaphragm)—8 of 12cases are positive.

[0948] (12) DNA261013 (TAT176)

[0949] With regard to normal tissues, prostate epithelium shows a weakpositive signal. Also, one core of colonic mucosa shows a weak signal inmucosal epithelium. Two cores of a testicular neoplasm are positive.

[0950] In another analysis, 87 cases of infiltrating ductal breastcancer are available for review. 40 cases are positive for expression.Additionally, all tested cell lines (A549, SK-MES, SKBR3, MDA231,MDA453, MDA175, MCF7) are positive for expression.

[0951] In another analysis, there is no consistent expression in benigncolon, small intestinal, liver, pancreatic, gastric or esophagealtissue. In malignant tumors expression is observed as follows:colorectal adenocarcinoma: 10 of 14 cases are positive, gastricadenocarcinoma: 4 of 8 cases are positive, esophageal carcinoma: 3 of 4cases are positive and metastatic adenocarcinoma: 8 of 11 cases arepositive.

[0952] (13) DNA262144 (TAT184)

[0953] Two of 4 cases of non-small cell lung carcinoma are positive forexpression while no signal is observed in non-neoplastic lung. In aseparate analysis, three cases of non-small cell lung carcinoma arepositive

[0954] (14) DNA267342 (TAT213)

[0955] Expression is not observed in any of the normal adult tissuestested. Seventy four cases of breast cancer are available for review and30 cases give a positive signal Expression localizes to tumor-associatedstroma.

[0956] In a separate analysis, expression is seen in a minority ofsarcomas; moderate and occasionally strong expression is seen in a caseof a synovial sarcoma, angiosarcoma, fibrosarcoma, gliosarcoma andmalignant fibrohistiocytoma. In most cases expression appears tolocalize to the malignant cell population.

[0957] (15) DNA267626 (TAT217)

[0958] Expression is seen in 6 of 9 invasive breast cancers. Expressionis in most cases of moderate intensity, expression is also seen inbenign mammary epithelium and fibroadenoma. The large sections includedin this study show expression in 1 of 1 endometrial adenocarcinomas, in2 of 3 invasive ductal breast cancers, in benign renal tubules, innormal breast epithelium and in epidermis. Sections of lung, brain,myometrium and eye are negative.

[0959] (16) DNA268334 (TAT202)

[0960] No expression is seen in any of the adult, normal tissues testedwhile expression is observed in 3 of 3 renal cell carcinomas.

[0961] (17) DNA269238 (TAT215)

[0962] Tumor-associated vasculature was strongly positive in all renalcell carcinomas tested (n=6), in all hepatocellular carcinomas tested(n=3), in all gastric adenocarcinomas tested (n=5), in all endometrialadenocarcinomas tested (n=3), in all malignant melanomas tested (n=3),in all malignant lymphomas tested (n=3), in all pancreaticadenocarcinomas tested (n=1), in all esophageal carcinomas tested (n=4),in all cholangiocarcinomas tested (n=2), in 93% of all non-small celllung cancers tested (n=15), in 86% of all invasive ductal breast cancerstested (n=88), in 83% of all colorectal adenocarcinomas tested (n=12),in 67% of all metastatic adenocarcinomas tested (n=6), in 75% of alltransitional cell carcinomas tested (n=4). While TAT215 expression isalso observed in endothelial components of various normal non-canceroustissues, the expression level is significantly lower in thesenon-cancerous tissues as compared to their cancerous counterparts andthe expression pattern in the tumor tissues was distinct from that inthe normal tissues, thereby providing a means for both therapy anddiagnosis of the cancerous condition.

[0963] (18) DNA304853 (TAT376)

[0964] With regard to normal tissues, it appears that there is a weaksignal in colon mucosa and breast epithelium. With regard to tumortissues, expression is seen in 1 of 2 non-small cell lung carcinomas, 2of 2 colon cancers, 1 of 2 pancreatic cancers, 1 of 2 hepatocellularcarcinomas, 3 of 3 endometrial carcinomas, 1 of 2 ovarian carcinomas and2 of 3 malignant melanomas.

[0965] In a separate analysis, 12 of 16 colorectal carcinomas arepositive for expression; 2 of 8 gastric adenocarcinoma are positive forexpression, 2 of 4 esophageal carcinomas are positive for expression; 7of 10 metastatic adenocarcinoma are positive for expression and 1 of 2cholangiocarcinomas are positive for expression. Expression level istumor tissues is consistently higher than in normal tissues.

[0966] (19) DNA304854 (TAT377)

[0967] With regard to normal tissues, it appears that there is a weaksignal in colon mucosa and breast epithelium. With regard to tumortissues, expression is seen in 1 of 2 non-small cell lung carcinomas, 2of 2 colon cancers, 1 of 2 pancreatic cancers, 1 of 2 hepatocellularcarcinomas, 3 of 3 endometrial carcinomas, 1 of 2 ovarian carcinomas and2 of 3 malignant melanomas.

[0968] In a separate analysis, 12 of 16 colorectal carcinomas arepositive for expression; 2 of 8 gastric adenocarcinoma are positive forexpression, 2 of 4 esophageal carcinomas are positive for expression; 7of 10 metastatic adenocarcinoma are positive for expression and 1 of 2cholangiocarcinomas are positive for expression. Expression level istumor tissues is consistently higher than in normal tissues.

[0969] (20) DNA304855 (TAT378)

[0970] With regard to normal tissues, it appears that there is a weaksignal in colon mucosa and breast epithelium. With regard to tumortissues, expression is seen in 1 of 2 non-small cell lung carcinomas, 2of 2 colon cancers, 1 of 2 pancreatic cancers, 1 of 2 hepatocellularcarcinomas, 3 of 3 endometrial carcinomas, 1 of 2 ovarian carcinomas and2 of 3 malignant melanomas.

[0971] In a separate analysis, 12 of 16 colorectal carcinomas arepositive for expression; 2 of 8 gastric adenocarcinoma are positive forexpression, 2 of 4 esophageal carcinomas are positive for expression; 7of 10 metastatic adenocarcinoma are positive for expression and 1 of 2cholangiocarcinomas are positive for expression. Expression level istumor tissues is consistently higher than in normal tissues.

[0972] (21) DNA287971 (TAT379)

[0973] With regard to normal tissues, strong expression is seen inprostatic epithelium and in a section of peripheral nerve. Moderateexpression is seen in renal glomeruli. Weak expression is seen in bileduct epithelium and mammary epithelium. Two sections of stomach showweak expression in a subset of gastric glands. Sections of colon andsmall intestine show a signal in lamina propria and/or submucosa, mostlikely in small autonomic nerve fibers. Another independent ISH studyfails to show expression in peripheral nerves of prostatectomy sections,despite adequate signal in prostatic epithelium.

[0974] In a separate analysis, 42 of 77 breast tumors are positive (55%)for expression.

[0975] In yet another analysis, 8 of 11 breast cancers are positive forexpression.

[0976] In yet another analysis, expression is seen in 1/2 non-small celllung carcinomas, 1/3 colorectal adenocarcinomas, 2/3 pancreaticadenocarcinomas, 1/1 prostate cancers, 1/3 transitional cell carcinomas,3/3 renal cell carcinomas, 3/3 endometrial adenocarcinomas, 1/2 ovarianadenocarcinomas and 1/3 malignant melanomas.

[0977] In yet another analysis, expression is seen in 42 of 45 (93%)prostate cancers.

[0978] In yet another analysis, expression is seen in all of 23 primaryand in 12 of 15 (80%) metastatic prostate cancers analyzed.

[0979] In yet another analysis, expression is observed in the followingcarcinomas as follows: pancreatic adenocarcinoma—2 of 2 cases arepositive; colorectal adenocarcinoma—12 of 14 cases are positive; gastricadenocarcinoma—6 of 8 cases are positive; esophageal carcinoma—2 of 3cases are positive; cholangiocarcinoma —1 of 1 case is positive;metastatic adenocarcinoma (ovary, liver, lymph node, diaphragm)—8 of 12cases are positive.

EXAMPLE 5 Verification and Analysis of Differential TAT PolypeptideExpression by GEPIS

[0980] TAT polypeptides which may have been identified as a tumorantigen as described in one or more of the above Examples were analyzedand verified as follows. An expressed sequence tag (EST) DNA database(LIFESEQ®, Incyte Pharmaceuticals, Palo Alto, Calif.) was searched andinteresting EST sequences were identified by GEPIS. Gene expressionprofilingin silico (GEPIS) is a bioinformatics tool developed atGenentech, Inc. that characterizes genes of interest for new cancertherapeutic targets. GEPIS takes advantage of large amounts of ESTsequence and library information to determine gene expression profiles.GEPIS is capable of determining the expression profile of a gene basedupon its proportional correlation with the number of its occurrences inEST databases, and it works by integrating the LIFESEQ® EST relationaldatabase and Genentech proprietary information in a stringent andstatistically meaningful way. In this example, GEPIS is used to identifyand cross-validate novel tumor antigens, although GEPIS can beconfigured to perform either very specific analyses or broad screeningtasks. For the initial screen, GEPIS is used to identify EST sequencesfrom the LIFESEQ® database that correlate to expression in a particulartissue or tissues of interest (often a tumor tissue of interest). TheEST sequences identified in this initial screen (or consensus sequencesobtained from aligning multiple related and overlapping EST sequencesobtained from the initial screen) were then subjected to a screenintended to identify the presence of at least one transmembrane domainin the encoded protein. Finally, GEPIS was employed to generate acomplete tissue expression profile for the various sequences ofinterest. Using this type of screening bioinformatics, various TATpolypeptides (and their encoding nucleic acid molecules) were identifiedas being significantly overexpressed in a particular type of cancer orcertain cancers as compared to other cancers and/or normal non-canceroustissues. The rating of GEPIS hits is based upon several criteriaincluding, for example, tissue specificity, tumor specificity andexpression level in normal essential and/or normal proliferatingtissues. The following is a list of molecules whose tissue expressionprofile as determined by GEPIS evidences high tissue expression andsignificant upregulation of expression in a specific tumor or tumors ascompared to other tumor(s) and/or normal tissues and optionallyrelatively low expression in normal essential and/or normalproliferating tissues. As such, the molecules listed below are excellentpolypeptide targets for the diagnosis and therapy of cancer in mammals.upregulation of Molecule expression in: as compared to: DNA67962(TAT207) colon tumor normal colon tissue DNA67962 (TAT207) uterus tumornormal uterus tissue DNA67962 (TAT207) lung tumor normal lung tissueDNA67962 (TAT207) prostate tumor normal prostate tissue DNA67962(TAT207) breast tumor normal breast tissue DNA96792 (TAT239) colon tumornormal colon tissue DNA96792 (TAT239) rectum tumor normal rectum tissueDNA96792 (TAT239) pancreas tumor normal pancreas tissue DNA96792(TAT239) lung tumor normal lung tissue DNA96792 (TAT239) stomach tumornormal stomach tissue DNA96792 (TAT239) esophagus tumor normal esophagustissue DNA96792 (TAT239) breast tumor normal breast tissue DNA96792(TAT239) uterus tumor normal uterus tissue DNA96964 (TAT193) breasttumor normal breast tissue DNA96964 (TAT193) brain tumor normal braintissue DNA142915 (TAT199) breast tumor normal breast tissue DNA142915(TAT199) ovary tumor normal ovary tissue DNA142915 (TAT199) brain tumornormal brain tissue DNA208551 (TAT178) prostate tumor normal prostatetissue DNA208551 (TAT178) colon tumor normal colon tissue DNA210159(TAT198) prostate tumor normal prostate tissue DNA210159 (TAT198) uterustumor normal uterus tissue DNA210159 (TAT198) breast tumor normal breasttissue DNA210159 (TAT198) ovarian tumor normal ovarian tissue DNA225706(TAT194) adrenal tumor normal adrenal tissue DNA225706 (TAT194) prostatetumor normal prostate tissue DNA225706 (TAT194) breast tumor normalbreast tissue DNA225706 (TAT194) connective tissue tumor normalconnective tissue DNA225793 (TAT223) ovarian tumor normal ovarian tissueDNA225793 (TAT223) fallopian tube normal fallopian tube tissue tumorDNA225793 (TAT223) kidney tumor normal kidney tissue DNA225796 (TAT196)breast tumor normal breast tissue DNA225943 (TAT195) liver tumor normalliver tissue DNA225943 (TAT195) lung tumor normal lung tissue DNA225943(TAT195) breast tumor normal breast tissue DNA226283 (TAT203) uterinetumor normal uterine tissue DNA226283 (TAT203) breast tumor normalbreast tissue DNA226283 (TAT203) squamous cell normal squamous cell lunglung tumor tissue DNA226283 (TAT203) colon tumor normal colon tissueDNA226283 (TAT203) ovarian tumor normal ovarian tissue DNA226589(TAT200) brain tumor normal brain tissue DNA226589 (TAT200) colon tumornormal colon tissue DNA226589 (TAT200) breast tumor normal breast tissueDNA226589 (TAT200) prostate tumor normal prostate tissue DNA226622(TAT205) squamous cell normal squamous cell lung lung tumor tissueDNA226622 (TAT205) kidney tumor normal kidney tissue DNA226622 (TAT205)uterine tumor normal uterine tissue DNA226622 (TAT205) breast tumornormal breast tissue DNA226622 (TAT205) colon tumor normal colon tissueDNA227545 (TAT197) breast tumor normal breast tissue DNA227611 (TAT175)prostate tumor normal prostate tissue DNA227611 (TAT175) colon tumornormal colon tissue DNA227611 (TAT175) breast tumor normal breast tissueDNA227611 (TAT175) uterine tumor normal uterine tissue DNA261021(TAT208) prostate tumor normal prostate tissue DNA261021 (TAT208) colontumor normal colon tissue DNA261021 (TAT208) breast tumor normal breasttissue DNA261021 (TAT208) uterine tumor normal uterine tissue DNA260655(TAT209) lung tumor normal lung tissue DNA260655 (TAT209) colon tumornormal colon tissue DNA260655 (TAT209) breast tumor normal breast tissueDNA260655 (TAT209) liver tumor normal liver tissue DNA260655 (TAT209)ovarian tumor normal ovarian tissue DNA260655 (TAT209) skin tumor normalskin tissue DNA260655 (TAT209) spleen tumor normal spleen tissueDNA260655 (TAT209) myeloid tumor normal myeloid tissue DNA260655(TAT209) muscle tumor normal muscle tissue DNA260655 (TAT209) bone tumornormal bone tissue DNA260945 (TAT192) brain tumor normal brain tissueDNA260945 (TAT192) breast tumor normal breast tissue DNA260945 (TAT192)colon tumor normal colon tissue DNA260945 (TAT192) ovarian tumor normalovarian tissue DNA260945 (TAT192) pancreatic tumor normal pancreatictissue DNA261001 (TAT181) bone tumor normal bone tissue DNA261001(TAT181) lung tumor normal lung tissue DNA266928 (TAT182) bone tumornormal bone tissue DNA266928 (TAT182) lung tumor normal lung tissueDNA268035 (TAT222) ovarian tumor normal ovarian tissue DNA277797(TAT212) breast tumor normal breast tissue DNA277797 (TAT212) pancreatictumor normal pancreatic tissue DNA77509 (TAT177) colon tumor normalcolon tissue DNA77509 (TAT177) testis tumor normal testis tissueDNA87993 (TAT235) breast tumor normal breast tissue DNA87993 (TAT235)prostate tumor normal prostate tissue DNA87993 (TAT235) colon tumornormal colon tissue DNA87993 (TAT235) ovarian tumor normal ovariantissue DNA92980 (TAT234) bone tumor normal bone tissue DNA92980 (TAT234)breast tumor normal breast tissue DNA92980 (TAT234) cervical tumornormal cervical tissue DNA92980 (TAT234) colon tumor normal colon tissueDNA92980 (TAT234) rectum tumor normal rectum tissue DNA92980 (TAT234)endometrial tumor normal endometrial tissue DNA92980 (TAT234) livertumor normal liver tissue DNA92980 (TAT234) lung tumor normal lungtissue DNA92980 (TAT234) ovarian tumor normal ovarian tissue DNA92980(TAT234) pancreatic tumor normal pancreatic tissue DNA92980 (TAT234)skin tumor normal skin tissue DNA92980 (TAT234) soft tissue tumor normalsoft tissue DNA92980 (TAT234) stomach tumor normal stomach tissueDNA92980 (TAT234) bladder tumor normal bladder tissue DNA92980 (TAT234)thyroid tumor normal thyroid tissue DNA92980 (TAT234) esophagus tumornormal esophagus tissue DNA92980 (TAT234) testis tumor normal testistissue DNA105792 (TAT233) adrenal tumor normal adrenal tissue DNA105792(TAT233) breast tumor normal breast tissue DNA105792 (TAT233)endometrial tumor normal endometrial tissue DNA105792 (TAT233) esophagustumor normal esophagus tissue DNA105792 (TAT233) kidney tumor normalkidney tissue DNA105792 (TAT233) lung tumor normal lung tissue DNA105792(TAT233) ovarian tumor normal ovarian tissue DNA105792 (TAT233)pancreatic tumor normal pancreatic tissue DNA105792 (TAT233) prostatetumor normal prostate tissue DNA105792 (TAT233) soft tissue tumor normalsoft tissue DNA105792 (TAT233) myeloid tumor normal myeloid tissueDNA105792 (TAT233) thyroid tumor normal thyroid tissue DNA105792(TAT233) bladder tumor normal bladder tissue DNA105792 (TAT233) braintumor normal brain tissue DNA105792 (TAT233) testis tumor normal testistissue DNA119474 (TAT226) kidney tumor normal kidney tissue DNA119474(TAT226) adrenal tumor normal adrenal tissue DNA119474 (TAT226) uterinetumor normal uterine tissue DNA119474 (TAT226) ovarian tumor normalovarian tissue DNA150491 (TAT204) squamous cell normal squamous celllung lung tumor tissue DNA150491 (TAT204) colon tumor normal colontissue DNA280351 (TAT248) squamous cell normal squamous cell lung lungtumor tissue DNA280351 (TAT248) colon tumor normal colon tissueDNA150648 (TAT232) liver tumor normal liver tissue DNA150648 (TAT232)breast tumor normal breast tissue DNA150648 (TAT232) brain tumor normalbrain tissue DNA150648 (TAT232) lung tumor normal lung tissue DNA150648(TAT232) colon tumor normal colon tissue DNA150648 (TAT232) rectum tumornormal rectum tissue DNA150648 (TAT232) kidney tumor normal kidneytissue DNA150648 (TAT232) bladder tumor normal bladder tissue DNA179651(TAT224) colon tumor normal colon tissue DNA179651 (TAT224) uterinetumor normal uterine tissue DNA179651 (TAT224) lung tumor normal lungtissue DNA179651 (TAT224) kidney tumor normal kidney tissue DNA225886(TAT236) breast tumor normal breast tissue DNA225886 (TAT236) colontumor normal colon tissue DNA225886 (TAT236) rectum tumor normal rectumtissue DNA225886 (TAT236) ovarian tumor normal ovarian tissue DNA225886(TAT236) pancreas tumor normal pancreas tissue DNA225886 (TAT236)prostate tumor normal prostate tissue DNA225886 (TAT236) bladder tumornormal bladder tissue DNA225886 (TAT236) testis tumor normal testistissue DNA226717 (TAT185) glioma normal glial tissue DNA226717 (TAT185)brain tumor normal brain tissue DNA227162 (TAT225) myeloid tumor normalmyeloid tissue DNA227162 (TAT225) uterine tumor normal uterine tissueDNA227162 (TAT225) prostate tumor normal prostate tissue DNA277804(TAT247) myeloid tumor normal myeloid tissue DNA277804 (TAT247) uterinetumor normal uterine tissue DNA277804 (TAT247) prostate tumor normalprostate tissue DNA233034 (TAT174) glioma normal glial tissue DNA233034(TAT174) brain tumor normal brain tissue DNA233034 (TAT174) kidney tumornormal kidney tissue DNA233034 (TAT174) adrenal tumor normal adrenaltissue DNA266920 (TAT214) glioma normal glial tissue DNA266920 (TAT214)brain tumor normal brain tissue DNA266920 (TAT214) kidney tumor normalkidney tissue DNA266920 (TAT214) adrenal tumor normal adrenal tissueDNA266921 (TAT220) glioma normal glial tissue DNA266921 (TAT220) braintumor normal brain tissue DNA266921 (TAT220) kidney tumor normal kidneytissue DNA266921 (TAT220) adrenal tumor normal adrenal tissue DNA266922(TAT221) glioma normal glial tissue DNA266922 (TAT221) brain tumornormal brain tissue DNA266922 (TAT221) kidney tumor normal kidney tissueDNA266922 (TAT221) adrenal tumor normal adrenal tissue DNA234834(TAT179) colon tumor normal colon tissue DNA234834 (TAT179) uterinetumor normal uterine tissue DNA234834 (TAT179) breast tumor normalbreast tissue DNA234834 (TAT179) prostate tumor normal prostate tissueDNA247587 (TAT216) breast tumor normal breast tissue DNA247587 (TAT216)prostate tumor normal prostate tissue DNA247587 (TAT216) bladder tumornormal bladder tissue DNA247587 (TAT216) lymphoid tumor normal lymphoidtissue DNA255987 (TAT218) brain tumor normal brain tissue DNA255987(TAT218) breast tumor normal breast tissue DNA247476 (TAT180) prostatetumor normal prostate tissue DNA247476 (TAT180) pancreas tumor normalpancreas tissue DNA247476 (TAT180) brain tumor normal brain tissueDNA247476 (TAT180) stomach tumor normal stomach tissue DNA247476(TAT180) bladder tumor normal bladder tissue DNA247476 (TAT180) softtissue tumor normal soft tissue DNA247476 (TAT180) skin tumor normalskin tissue DNA247476 (TAT180) kidney tumor normal kidney tissueDNA260990 (TAT375) prostate tumor normal prostate tissue DNA260990(TAT375) pancreas tumor normal pancreas tissue DNA260990 (TAT375) braintumor normal brain tissue DNA260990 (TAT375) stomach tumor normalstomach tissue DNA260990 (TAT375) bladder tumor normal bladder tissueDNA260990 (TAT375) soft tissue tumor normal soft tissue DNA260990(TAT375) skin tumor normal skin tissue DNA260990 (TAT375) kidney tumornormal kidney tissue DNA261013 (TAT176) prostate tumor normal prostatetissue DNA261013 (TAT176) colon tumor normal colon tissue DNA261013(TAT176) small intestine normal small intestine tissue tumor DNA261013(TAT176) pancreatic tumor normal pancreatic tissue DNA261013 (TAT176)uterine tumor normal uterine tissue DNA261013 (TAT176) ovarian tumornormal ovarian tissue DNA261013 (TAT176) bladder tumor normal bladdertissue DNA261013 (TAT176) stomach tumor normal stomach tissue DNA267342(TAT213) breast tumor normal breast tissue DNA267342 (TAT213) uterinetumor normal uterine tissue DNA267342 (TAT213) colon tumor normal colontissue DNA267342 (TAT213) kidney tumor normal kidney tissue DNA267342(TAT213) bladder tumor normal bladder tissue DNA267342 (TAT213) bonetumor normal bone tissue DNA267342 (TAT213) ovarian tumor normal ovariantissue DNA267342 (TAT213) pancreatic tumor normal pancreatic tissueDNA267626 (TAT217) breast tumor normal breast tissue DNA267626 (TAT217)colon tumor normal colon tissue DNA267626 (TAT217) pancreatic tumornormal pancreatic tissue DNA267626 (TAT217) ovarian tumor normal ovariantissue DNA268334 (TAT202) kidney tumor normal kidney tissue DNA269238(TAT215) colon tumor normal colon tissue DNA269238 (TAT215) kidney tumornormal kidney tissue DNA269238 (TAT215) adrenal tumor normal adrenaltissue DNA269238 (TAT215) bladder tumor normal bladder tissue DNA272578(TAT238) adrenal tumor normal adrenal tissue DNA272578 (TAT238) lungtumor normal lung tissue DNA272578 (TAT238) ovarian tumor normal ovariantissue DNA272578 (TAT238) uterine tumor normal uterine tissue DNA304853(TAT376) colon tumor normal colon tissue DNA304853 (TAT376) uterinetumor normal uterine tissue DNA304853 (TAT376) breast tumor normalbreast tissue DNA304853 (TAT376) prostate tumor normal prostate tissueDNA304854 (TAT377) colon tumor normal colon tissue DNA304854 (TAT377)uterine tumor normal uterine tissue DNA304854 (TAT377) breast tumornormal breast tissue DNA304854 (TAT377) prostate tumor normal prostatetissue DNA304855 (TAT378) colon tumor normal colon tissue DNA304855(TAT378) uterine tumor normal uterine tissue DNA304855 (TAT378) breasttumor normal breast tissue DNA304855 (TAT378) prostate tumor normalprostate tissue DNA287971 (TAT379) prostate tumor normal prostate tissueDNA287971 (TAT379) pancreas tumor normal pancreas tissue DNA287971(TAT379) brain tumor normal brain tissue DNA287971 (TAT379) stomachtumor normal stomach tissue DNA287971 (TAT379) bladder tumor normalbladder tissue DNA287971 (TAT379) soft tissue tumor normal soft tissueDNA287971 (TAT379) skin tumor normal skin tissue DNA287971 (TAT379)kidney tumor normal kidney tissue

EXAMPLE 6 Use of TAT as a Hybridization Probe

[0981] The following method describes use of a nucleotide sequenceencoding TAT as a hybridization probe for, i.e., diagnosis of thepresence of a tumor in a mammal.

[0982] DNA comprising the coding sequence of full-length or mature TATas disclosed herein can also be employed as a probe to screen forhomologous DNAs (such as those encoding naturally-occurring variants ofTAT) in human tissue cDNA libraries or human tissue genomic libraries.

[0983] Hybridization and washing of filters containing either libraryDNAs is performed under the following high stringency conditions.Hybridization of radiolabeled TAT-derived probe to the filters isperformed in a solution of 50% formamide, 5×SSC, 0.1% SDS, 0.1% sodiumpyrophosphate, 50 mM sodium phosphate, pH 6.8, 2× Denhardt's solution,and 10% dextran sulfate at 42° C. for 20 hours. Washing of the filtersis performed in an aqueous solution of 0.1×SSC and 0.1% SDS at 42° C.

[0984] DNAs having a desired sequence identity with the DNA encodingfull-length native sequence TAT can then be identified using standardtechniques known in the art.

EXAMPLE 7 Expression of TAT in E. coli

[0985] This example illustrates preparation of an unglycosylated form ofTAT by recombinant expression in E. coli.

[0986] The DNA sequence encoding TAT is initially amplified usingselected PCR primers. The primers should contain restriction enzymesites which correspond to the restriction enzyme sites on the selectedexpression vector. A variety of expression vectors may be employed. Anexample of a suitable vector is pBR322 (derived from E. coli; seeBolivar et al., Gene, 2:95 (1977)) which contains genes for ampicillinand tetracycline resistance. The vector is digested with restrictionenzyme and dephosphorylated. The PCR amplified sequences are thenligated into the vector. The vector will preferably include sequenceswhich encode for an antibiotic resistance gene, a trp promoter, apolyhis leader (including the first six STII codons, polyhis sequence,and enterokinase cleavage site), the TAT coding region, lambdatranscriptional terminator, and an argU gene.

[0987] The ligation mixture is then used to transform a selected E. colistrain using the methods described in Sambrook et al., supra.Transformants are identified by their ability to grow on LB plates andantibiotic resistant colonies are then selected. Plasmid DNA can beisolated and confirmed by restriction analysis and DNA sequencing.

[0988] Selected clones can be grown overnight in liquid culture mediumsuch as LB broth supplemented with antibiotics. The overnight culturemay subsequently be used to inoculate a larger scale culture. The cellsare then grown to a desired optical density, during which the expressionpromoter is turned on.

[0989] After culturing the cells for several more hours, the cells canbe harvested by centrifugation. The cell pellet obtained by thecentrifugation can be solubilized using various agents known in the art,and the solubilized TAT protein can then be purified using a metalchelating column under conditions that allow tight binding of theprotein.

[0990] TAT may be expressed in E. coli in a poly-His tagged form, usingthe following procedure. The DNA encoding TAT is initially amplifiedusing selected PCR primers. The primers will contain restriction enzymesites which correspond to the restriction enzyme sites on the selectedexpression vector, and other useful sequences providing for efficientand reliable translation initiation, rapid purification on a metalchelation column, and proteolytic removal with enterokinase. ThePCR-amplified, poly-His tagged sequences are then ligated into anexpression vector, which is used to transform an E. coli host based onstrain 52 (W3110 fuhA(tonA) 1on galE rpoHts(htpRts) clpP(lacIq).Transformants are first grown in LB containing 50 mg/ml carbenicillin at30° C. with shaking until an O.D.600 of 3-5 is reached. Cultures arethen diluted 50-100 fold into CRAP media (prepared by mixing 3.57 g(NH₄)₂SO₄, 0.71 g sodium citrate. 2H2O, 1.07 g KCl, 5.36 g Difco yeastextract, 5.36 g Sheffield hycase SF in 500 mL water, as well as 110 mMMPOS, pH 7.3, 0.55% (w/v) glucose and 7 mM MgSO₄) and grown forapproximately 20-30 hours at 30° C. with shaking. Samples are removed toverify expression by SDS-PAGE analysis, and the bulk culture iscentrifuged to pellet the cells. Cell pellets are frozen untilpurification and refolding.

[0991]E. coli paste from 0.5 to 1 L fermentations (6-10 g pellets) isresuspended in 10 volumes (w/v) in 7 M guanidine, 20 mM Tris, pH 8buffer. Solid sodium sulfite and sodium tetrathionate is added to makefinal concentrations of 0.1M and 0.02M, respectively, and the solutionis stirred overnight at 4° C. This step results in a denatured proteinwith all cysteine residues blocked by sulfitolization. The solution iscentrifuged at 40,000 rpm in a Beckman Ultracentifuge for 30 min. Thesupernatant is diluted with 3-5 volumes of metal chelate column buffer(6 M guanidine, 20 mM Tris, pH 7.4) and filtered through 0.22 micronfilters to clarify. The clarified extract is loaded onto a 5 ml QiagenNi-NTA metal chelate column equilibrated in the metal chelate columnbuffer. The column is washed with additional buffer containing 50 mMimidazole (Calbiochem, Utrol grade), pH 7.4. The protein is eluted withbuffer containing 250 mM imidazole. Fractions containing the desiredprotein are pooled and stored at 4° C. Protein concentration isestimated by its absorbance at 280 nm using the calculated extinctioncoefficient based on its amino acid sequence.

[0992] The proteins are refolded by diluting the sample slowly intofreshly prepared refolding buffer consisting of: 20 mM Tris, pH 8.6, 0.3M NaCl, 2.5 M urea, 5 mM cysteine, 20 mM glycine and 1 mM EDTA.Refolding volumes are chosen so that the final protein concentration isbetween 50 to 100 micrograms/ml. The refolding solution is stirredgently at 4° C. for 12-36 hours. The refolding reaction is quenched bythe addition of TFA to a final concentration of 0.4% (pH ofapproximately 3). Before further purification of the protein, thesolution is filtered through a 0.22 micron filter and acetonitrile isadded to 2-10% final concentration. The refolded protein ischromatographed on a Poros R 1/H reversed phase column using a mobilebuffer of 0.1% TFA with elution with a gradient of acetonitrile from 10to 80%. Aliquots of fractions with A280 absorbance are analyzed on SDSpolyacrylamide gels and fractions containing homogeneous refoldedprotein are pooled. Generally, the properly refolded species of mostproteins are eluted at the lowest concentrations of acetonitrile sincethose species are the most compact with their hydrophobic interiorsshielded from interaction with the reversed phase resin. Aggregatedspecies are usually eluted at higher acetonitrile concentrations. Inaddition to resolving misfolded forms of proteins from the desired form,the reversed phase step also removes endotoxin from the samples.

[0993] Fractions containing the desired folded TAT polypeptide arepooled and the acetonitrile removed using a gentle stream of nitrogendirected at the solution. Proteins are formulated into 20 mM Hepes, pH6.8 with 0. 14 M sodium chloride and 4% mannitol by dialysis or by gelfiltration using G25 Superfine (Pharmacia) resins equilibrated in theformulation buffer and sterile filtered.

[0994] Certain of the TAT polypeptides disclosed herein have beensuccessfully expressed and purified using this technique(s).

EXAMPLE 8 Expression of TAT in Mammalian Cells

[0995] This example illustrates preparation of a potentiallyglycosylated form of TAT by recombinant expression in mammalian cells.

[0996] The vector, pRK5 (see EP 307,247, published Mar. 15, 1989), isemployed as the expression vector. Optionally, the TAT DNA is ligatedinto pRK5 with selected restriction enzymes to allow insertion of theTAT DNA using ligation methods such as described in Sambrook et al.,supra. The resulting vector is called pRK5-TAT.

[0997] In one embodiment, the selected host cells may be 293 cells.Human 293 cells (ATCC CCL 1573) are grown to confluence in tissueculture plates in medium such as DMEM supplemented with fetal calf serumand optionally, nutrient components and/or antibiotics. About 10 μgpRK5-TAT DNA is mixed with about 1 μg DNA encoding the VA RNA gene[Thimmappaya et al., Cell, 31:543 (1982)] and dissolved in 500 μl of 1mM Tris-HCl, 0.1 mM EDTA, 0.227 M CaCl₂. To this mixture is added,dropwise, 500 μl of 50 mM HEPES (pH 7.35), 280 mM NaCl, 1.5 mM NaPO₄,and a precipitate is allowed to form for 10 minutes at 25° C. Theprecipitate is suspended and added to the 293 cells and allowed tosettle for about four hours at 37° C. The culture medium is aspiratedoff and 2 ml of 20% glycerol in PBS is added for 30 seconds. The 293cells are then washed with serum free medium, fresh medium is added andthe cells are incubated for about 5 days.

[0998] Approximately 24 hours after the transfections, the culturemedium is removed and replaced with culture medium (alone) or culturemedium containing 200 μCi/ml ³⁵S-cysteine and 200 μCi/ml ³⁵S-methionine.After a 12 hour incubation, the conditioned medium is collected,concentrated on a spin filter, and loaded onto a 15% SDS gel. Theprocessed gel may be dried and exposed to film for a selected period oftime to reveal the presence of TAT polypeptide. The cultures containingtransfected cells may undergo further incubation (in serum free medium)and the medium is tested in selected bioassays.

[0999] In an alternative technique, TAT may be introduced into 293 cellstransiently using the dextran sulfate method described by Somparyrac etal., Proc. Natl. Acad. Sci., 12:7575 (1981). 293 cells are grown tomaximal density in a spinner flask and 700 μg pRK5-TAT DNA is added. Thecells are first concentrated from the spinner flask by centrifugationand washed with PBS. The DNA-dextran precipitate is incubated on thecell pellet for four hours. The cells are treated with 20% glycerol for90 seconds, washed with tissue culture medium, and re-introduced intothe spinner flask containing tissue culture medium, 5 μg/ml bovineinsulin and 0.1 μg/ml bovine transferrin. After about four days, theconditioned media is centrifuged and filtered to remove cells anddebris. The sample containing expressed TAT can then be concentrated andpurified by any selected method, such as dialysis and/or columnchromatography.

[1000] In another embodiment, TAT can be expressed in CHO cells. ThepRK5-TAT can be transfected into CHO cells using known reagents such asCaPO₄ or DEAE-dextran. As described above, the cell cultures can beincubated, and the medium replaced with culture medium (alone) or mediumcontaining a radiolabel such as ³⁵S-methionine. After determining thepresence of TAT polypeptide, the culture medium may be replaced withserum free medium. Preferably, the cultures are incubated for about 6days, and then the conditioned medium is harvested. The mediumcontaining the expressed TAT can then be concentrated and purified byany selected method.

[1001] Epitope-tagged TAT may also be expressed in host CHO cells. TheTAT may be subcloned out of the pRK5 vector. The subclone insert canundergo PCR to fuse in frame with a selected epitope tag such as apoly-his tag into a Baculovirus expression vector. The poly-his taggedTAT insert can then be subcloned into a SV40 driven vector containing aselection marker such as DHFR for selection of stable clones. Finally,the CHO cells can be transfected (as described above) with the SV40driven vector. Labeling may be performed, as described above, to verifyexpression. The culture medium containing the expressed poly-His taggedTAT can then be concentrated and purified by any selected method, suchas by Ni²⁺-chelate affinity chromatography.

[1002] TAT may also be expressed in CHO and/or COS cells by a transientexpression procedure or in CHO cells by another stable expressionprocedure.

[1003] Stable expression in CHO cells is performed using the followingprocedure. The proteins are expressed as an IgG construct(immunoadhesin), in which the coding sequences for the soluble forms(e.g. extracellular domains) of the respective proteins are fused to anIgGl constant region sequence containing the hinge, CH2 and CH2 domainsand/or is a poly-His tagged form.

[1004] Following PCR amplification, the respective DNAs are subcloned ina CHO expression vector using standard techniques as described inAusubel et al., Current Protocols of Molecular Biology, Unit 3.16, JohnWiley and Sons (1997). CHO expression vectors are constructed to havecompatible restriction sites 5′ and 3′ of the DNA of interest to allowthe convenient shuttling of cDNA's. The vector used expression in CHOcells is as described in Lucas et al., Nucl. Acids Res. 24:9 (1774-1779(1996), and uses the SV40 early promoter/enhancer to drive expression ofthe CDNA of interest and dihydrofolate reductase (DHFR). DHFR expressionpermits selection for stable maintenance of the plasmid followingtransfection.

[1005] Twelve micrograms of the desired plasmid DNA is introduced intoapproximately 10 million CHO cells using commercially availabletransfection reagents Superfect® (Quiagen), Dosper® or Fugene®(Boehringer Mannheim). The cells are grown as described in Lucas etal.supra. Approximately 3×10⁷ cells are frozen in an ampule for furthergrowth and production as described below.

[1006] The ampules containing the plasmid DNA are thawed by placementinto water bath and mixed by vortexing. The contents are pipetted into acentrifuge tube containing 10 mLs of media and centrifuged at 1000 rpmfor 5 minutes. The supernatant is aspirated and the cells areresuspended in 10 mL of selective media (0.2 μm filtered PS20 with 5%0.2 μm diafiltered fetal bovine serum). The cells are then aliquotedinto a 100 spinner containing 90 mL of selective media. After 1-2 days,the cells are transferred into a 250 mL spinner filled with 150 mLselective growth medium and incubated at 37° C. After another 2-3 days,250 mL, 500 mL and 2000 mL spinners are seeded with 3×10⁵ cells/mL. Thecell media is exchanged with fresh media by centrifugation andresuspension in production medium. Although any suitable CHO media maybe employed, a production medium described in U.S. Pat. No. 5,122,469,issued Jun. 16, 1992 may actually be used. A 3L production spinner isseeded at 1.2×10⁶ cells/mL. On day 0, the cell number pH ie determined.On day 1, the spinner is sampled and sparging with filtered air iscommenced. On day 2, the spinner is sampled, the temperature shifted to33° C., and 30 mL of 500 g/L glucose and 0.6 mL of 10% antifoam (e.g.,35% polydimethylsiloxane emulsion, Dow Corning 365 Medical GradeEmulsion) taken. Throughout the production, the pH is adjusted asnecessary to keep it at around 7.2. After 10 days, or until theviability dropped below 70%, the cell culture is harvested bycentrifugation and filtering through a 0.22 μm filter. The filtrate waseither stored at 4° C. or immediately loaded onto columns forpurification.

[1007] For the poly-His tagged constructs, the proteins are purifiedusing a Ni-NTA column (Qiagen). Before purification, imidazole is addedto the conditioned media to a concentration of 5 mM. The conditionedmedia is pumped onto a 6 ml Ni-NTA column equilibrated in 20 mM Hepes,pH 7.4, buffer containing 0.3 M NaCl and 5 mM imidazole at a flow rateof 4-5 m/min. at 4° C. After loading, the column is washed withadditional equilibration buffer and the protein eluted withequilibration buffer containing 0.25 M imidazole. The highly purifiedprotein is subsequently desalted into a storage buffer containing 10 mMHepes, 0.14 M NaCl and 4% mannitol, pH 6.8, with a 25 ml G25 Superfine(Pharmacia) column and stored at −80° C.

[1008] Immunoadhesin (Fc-containing) constructs are purified from theconditioned media as follows. The conditioned medium is pumped onto a 5ml Protein A column (Pharmacia) which had been equilibrated in 20 mM Naphosphate buffer, pH 6.8. After loading, the column is washedextensively with equilibration buffer before elution with 100 mM citricacid, pH 3.5. The eluted protein is immediately neutralized bycollecting 1 ml fractions into tubes containing 275 μL of 1 M Trisbuffer, pH 9. The highly purified protein is subsequently desalted intostorage buffer as described above for the poly-His tagged proteins. Thehomogeneity is assessed by SDS polyacrylamide gels and by N-terminalamino acid sequencing by Edman degradation.

[1009] Certain of the TAT polypeptides disclosed herein have beensuccessfully expressed and purified using this technique(s).

EXAMPLE 9 Expression of TAT in Yeast

[1010] The following method describes recombinant expression of TAT inyeast.

[1011] First, yeast expression vectors are constructed for intracellularproduction or secretion of TAT from the ADH2/GAPDH promoter. DNAencoding TAT and the promoter is inserted into suitable restrictionenzyme sites in the selected plasmid to direct intracellular expressionof TAT. For secretion, DNA encoding TAT can be cloned into the selectedplasmid, together with DNA encoding the ADH2/GAPDH promoter, a nativeTAT signal peptide or other mammalian signal peptide, or, for example, ayeast alpha-factor or invertase secretory signal/leader sequence, andlinker sequences (if needed) for expression of TAT.

[1012] Yeast cells, such as yeast strain AB 110, can then be transformedwith the expression plasmids described above and cultured in selectedfermentation media. The transformed yeast supernatants can be analyzedby precipitation with 10% trichloroacetic acid and separation bySDS-PAGE, followed by staining of the gels with Coomassie Blue stain.

[1013] Recombinant TAT can subsequently be isolated and purified byremoving the yeast cells from the fermentation medium by centrifugationand then concentrating the medium using selected cartridge filters. Theconcentrate containing TAT may further be purified using selected columnchromatography resins.

[1014] Certain of the TAT polypeptides disclosed herein have beensuccessfully expressed and purified using this technique(s).

EXAMPLE 10 Expression of TAT in Baculovirus-Infected Insect Cells

[1015] The following method describes recombinant expression of TAT inBaculovirus-infected insect cells.

[1016] The sequence coding for TAT is fused upstream of an epitope tagcontained within a baculovirus expression vector. Such epitope tagsinclude poly-his tags and immunoglobulin tags (like Fc regions of IgG).A variety of plasmids may be employed, including plasmids derived fromcommercially available plasmids such as pVL1393 (Novagen). Briefly, thesequence encoding TAT or the desired portion of the coding sequence ofTAT such as the sequence encoding an extracellular domain of atransmembrane protein or the sequence encoding the mature protein if theprotein is extracellular is amplified by PCR with primers complementaryto the 5′ and 3′ regions. The 5′ primer may incorporate flanking(selected) restriction enzyme sites. The product is then digested withthose selected restriction enzymes and subcloned into the expressionvector.

[1017] Recombinant baculovirus is generated by co-transfecting the aboveplasmid and BaculoGold™ virus DNA (Pharmingen) into Spodopterafrugiperda (“Sf9”) cells (ATCC CRL 1711) using lipofectin (commerciallyavailable from GIBCO-BRL). After 4-5 days of incubation at 28 C, thereleased viruses are harvested and used for further amplifications.Viral infection and protein expression are performed as described byO'Reilley et al., Baculovirus expression vectors: A Laboratory Manual,Oxford: Oxford University Press (1994).

[1018] Expressed poly-his tagged TAT can then be purified, for example,by Ni²⁺-chelate affinity chromatography as follows. Extracts areprepared from recombinant virus-infected Sf9 cells as described byRupert et al., Nature, 362:175-179 (1993). Briefly, Sf9 cells arewashed, resuspended in sonication buffer (25 mL Hepes, pH 7.9; 12.5 mMMgCl₂; 0.1 mM EDTA; 10% glycerol; 0.1% NP-40; 0.4 M KCl), and sonicatedtwice for 20 seconds on ice. The sonicates are cleared bycentrifugation, and the supernatant is diluted 50-fold in loading buffer(50 mM phosphate, 300 mM NaCl, 10% glycerol, pH 7.8) and filteredthrough a 0.45 μm filter. A Ni²⁺-NTA agarose column (commerciallyavailable from Qiagen) is prepared with a bed volume of 5 mL, washedwith 25 mL of water and equilibrated with 25 mL of loading buffer. Thefiltered cell extract is loaded onto the column at 0.5 mL per minute.The column is washed to baseline A₂₈₀ with loading buffer, at whichpoint fraction collection is started. Next, the column is washed with asecondary wash buffer (50 mM phosphate; 300 mM NaCl, 10% glycerol, pH6.0), which elutes nonspecifically bound protein. After reaching A₂₈₀baseline again, the column is developed with a 0 to 500 mM Imidazolegradient in the secondary wash buffer. One mL fractions are collectedand analyzed by SDS-PAGE and silver staining or Western blot with

NTA-conjugated to alkaline phosphatase (Qiagen). Fractions containingthe eluted His₁₀-tagged TAT are pooled and dialyzed against loadingbuffer.

[1019] Alternatively, purification of the IgG tagged (or Fc tagged) TATcan be performed using known chromatography techniques, including forinstance, Protein A or protein G column chromatography.

[1020] Certain of the TAT polypeptides disclosed herein have beensuccessfully expressed and purified using this technique(s).

EXAMPLE 11 Preparation of Antibodies that Bind TAT

[1021] This example illustrates preparation of monoclonal antibodieswhich can specifically bind TAT.

[1022] Techniques for producing the monoclonal antibodies are known inthe art and are described, for instance, in Goding, supra. Immunogensthat may be employed include purified TAT, fusion proteins containingTAT, and cells expressing recombinant TAT on the cell surface. Selectionof the immunogen can be made by the skilled artisan without undueexperimentation.

[1023] Mice, such as Balb/c, are immunized with the TAT immunogenemulsified in complete Freund's adjuvant and injected subcutaneously orintraperitoneally in an amount from 1-100 micrograms. Alternatively, theimmunogen is emulsified in MPL-TDM adjuvant (Ribi ImmunochemicalResearch, Hamilton, Mont.) and injected into the animal's hind footpads. The immunized mice are then boosted 10 to 12 days later withadditional immunogen emulsified in the selected adjuvant. Thereafter,for several weeks, the mice may also be boosted with additionalimmunization injections. Serum samples may be periodically obtained fromthe mice by retro-orbital bleeding for testing in ELISA assays to detectanti-TAT antibodies.

[1024] After a suitable antibody titer has been detected, the animals“positive” for antibodies can be injected with a final intravenousinjection of TAT. Three to four days later, the mice are sacrificed andthe spleen cells are harvested. The spleen cells are then fused (using35% polyethylene glycol) to a selected murine myeloma cell line such asP3X63AgU.1, available from ATCC, No. CRL 1597. The fusions generatehybridoma cells which can then be plated in 96 well tissue cultureplates containing HAT (hypoxanthine, aminopterin, and thymidine) mediumto inhibit proliferation of non-fused cells, myeloma hybrids, and spleencell hybrids.

[1025] The hybridoma cells will be screened in an ELISA for reactivityagainst TAT. Determination of “positive” hybridoma cells secreting thedesired monoclonal antibodies against TAT is within the skill in theart.

[1026] The positive hybridoma cells can be injected intraperitoneallyinto syngeneic Balb/c mice to produce ascites containing the anti-TATmonoclonal antibodies. Alternatively, the hybridoma cells can be grownin tissue culture flasks or roller bottles. Purification of themonoclonal antibodies produced in the ascites can be accomplished usingammonium sulfate precipitation, followed by gel exclusionchromatography. Alternatively, affinity chromatography based uponbinding of antibody to protein A or protein G can be employed.

EXAMPLE 12 Purification of TAT Polypeptides Using Specific Antibodies

[1027] Native or recombinant TAT polypeptides may be purified by avariety of standard techniques in the art of protein purification. Forexample, pro-TAT polypeptide, mature TAT polypeptide, or pre-TATpolypeptide is purified by immunoaffinity chromatography usingantibodies specific for the TAT polypeptide of interest. In general, animmunoaffinity column is constructed by covalently coupling the anti-TATpolypeptide antibody to an activated chromatographic resin.

[1028] Polyclonal immunoglobulins are prepared from immune sera eitherby precipitation with ammonium sulfate or by purification on immobilizedProtein A (Pharmacia LKB Biotechnology, Piscataway, N.J.). Likewise,monoclonal antibodies are prepared from mouse ascites fluid by ammoniumsulfate precipitation or chromatography on immobilized Protein A.Partially purified immunoglobulin is covalently attached to achromatographic resin such as CnBr-activated SEPHAROSE™ (Pharmacia LKBBiotechnology). The antibody is coupled to the resin, the resin isblocked, and the derivative resin is washed according to themanufacturer's instructions.

[1029] Such an immunoaffinity column is utilized in the purification ofTAT polypeptide by preparing a fraction from cells containing TATpolypeptide in a soluble form. This preparation is derived bysolubilization of the whole cell or of a subcellular fraction obtainedvia differential centrifugation by the addition of detergent or by othermethods well known in the art. Alternatively, soluble TAT polypeptidecontaining a signal sequence may be secreted in useful quantity into themedium in which the cells are grown.

[1030] A soluble TAT polypeptide-containing preparation is passed overthe immunoaffinity column, and the column is washed under conditionsthat allow the preferential absorbance of TAT polypeptide ( e.g., highionic strength buffers in the presence of detergent). Then, the columnis eluted under conditions that disrupt antibody/TAT polypeptide binding(e.g., a low pH buffer such as approximately pH 2-3, or a highconcentration of a chaotrope such as urea or thiocyanate ion), and TATpolypeptide is collected.

EXAMPLE 13 In Vitro Tumor Cell Killing Assay

[1031] Mammalian cells expressing the TAT polypeptide of interest may beobtained using standard expression vector and cloning techniques.Alternatively, many tumor cell lines expressing TAT polypeptides ofinterest are publicly available, for example, through the ATCC and canbe routinely identified using standard ELISA or FACS analysis. Anti-TATpolypeptide monoclonal antibodies (and toxin conjugated derivativesthereof) may then be employed in assays to determine the ability of theantibody to kill TAT polypeptide expressing cells in vitro.

[1032] For example, cells expressing the TAT polypeptide of interest areobtained as described above and plated into 96 well dishes. In oneanalysis, the antibody/toxin conjugate (or naked antibody) is includedthroughout the cell incubation for a period of 4 days. In a secondindependent analysis, the cells are incubated for 1 hour with theantibody/toxin conjugate (or naked antibody) and then washed andincubated in the absence of antibody/toxin conjugate for a period of 4days. Cell viability is then measured using the CellTiter-GloLuminescent Cell Viability Assay from Promega (Cat#G7571). Untreatedcells serve as a negative control.

EXAMPLE 14 In Vivo Tumor Cell Killing Assay

[1033] To test the efficacy of conjugated or unconjugated anti-TATpolypeptide monoclonal antibodies, anti-TAT antibody is injectedintraperitoneally into nude mice 24 hours prior to receiving tumorpromoting cells subcutaneously in the flank. Antibody injectionscontinue twice per week for the remainder of the study. Tumor volume isthen measured twice per week.

[1034] The assignee of the present application has agreed that if aculture of the materials on deposit should die or be lost or destroyedwhen cultivated under suitable conditions, the materials will bepromptly replaced on notification with another of the same. Availabilityof the deposited material is not to be construed as a license topractice the invention in contravention of the rights granted under theauthority of any government in accordance with its patent laws.

[1035] The foregoing written specification is considered to besufficient to enable one skilled in the art to practice the invention.The present invention is not to be limited in scope by the constructdeposited, since the deposited embodiment is intended as a singleillustration of certain aspects of the invention and any constructs thatare functionally equivalent are within the scope of this invention. Thedeposit of material herein does not constitute an admission that thewritten description herein contained is inadequate to enable thepractice of any aspect of the invention, including the best modethereof, nor is it to be construed as limiting the scope of the claimsto the specific illustrations that it represents. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art from theforegoing description and fall within the scope of the appended claims.

1 120 1 3781 DNA Homo Sapien 1 ctccgggtcc ccaggggctg cgccgggccggcctggcaag ggggacgagt 50 cagtggacac tccaggaaga gcggccccgc ggggggcgatgaccgtgcgc 100 tgaccctgac tcactccagg tccggaggcg ggggcccccg gggcgactcg150 ggggcggacc gcggggcgga gctgccgccc gtgagtccgg ccgagccacc 200tgagcccgag ccgcgggaca ccgtcgctcc tgctctccga atgctgcgca 250 ccgcgatgggcctgaggagc tggctcgccg ccccatgggg cgcgctgccg 300 cctcggccac cgctgctgctgctcctgctg ctgctgctcc tgctgcagcc 350 gccgcctccg acctgggcgc tcagcccccggatcagcctg cctctgggct 400 ctgaagagcg gccattcctc agattcgaag ctgaacacatctccaactac 450 acagcccttc tgctgagcag ggatggcagg accctgtacg tgggtgctcg500 agaggccctc tttgcactca gtagcaacct cagcttcctg ccaggcgggg 550agtaccagga gctgctttgg ggtgcagacg cagagaagaa acagcagtgc 600 agcttcaagggcaaggaccc acagcgcgac tgtcaaaact acatcaagat 650 cctcctgccg ctcagcggcagtcacctgtt cacctgtggc acagcagcct 700 tcagccccat gtgtacctac atcaacatggagaacttcac cctggcaagg 750 gacgagaagg ggaatgtcct cctggaagat ggcaagggccgttgtccctt 800 cgacccgaat ttcaagtcca ctgccctggt ggttgatggc gagctctaca850 ctggaacagt cagcagcttc caagggaatg acccggccat ctcgcggagc 900caaagccttc gccccaccaa gaccgagagc tccctcaact ggctgcaaga 950 cccagcttttgtggcctcag cctacattcc tgagagcctg ggcagcttgc 1000 aaggcgatga tgacaagatctactttttct tcagcgagac tggccaggaa 1050 tttgagttct ttgagaacac cattgtgtcccgcattgccc gcatctgcaa 1100 gggcgatgag ggtggagagc gggtgctaca gcagcgctggacctccttcc 1150 tcaaggccca gctgctgtgc tcacggcccg acgatggctt ccccttcaac1200 gtgctgcagg atgtcttcac gctgagcccc agcccccagg actggcgtga 1250cacccttttc tatggggtct tcacttccca gtggcacagg ggaactacag 1300 aaggctctgccgtctgtgtc ttcacaatga aggatgtgca gagagtcttc 1350 agcggcctct acaaggaggtgaaccgtgag acacagcagt ggtacaccgt 1400 gacccacccg gtgcccacac cccggcctggagcgtgcatc accaacagtg 1450 cccgggaaag gaagatcaac tcatccctgc agctcccagaccgcgtgctg 1500 aacttcctca aggaccactt cctgatggac gggcaggtcc gaagccgcat1550 gctgctgctg cagccccagg ctcgctacca gcgcgtggct gtacaccgcg 1600tccctggcct gcaccacacc tacgatgtcc tcttcctggg cactggtgac 1650 ggccggctccacaaggcagt gagcgtgggc ccccgggtgc acatcattga 1700 ggagctgcag atcttctcatcgggacagcc cgtgcagaat ctgctcctgg 1750 acacccacag ggggctgctg tatgcggcctcacactcggg cgtagtccag 1800 gtgcccatgg ccaactgcag cctgtaccgg agctgtggggactgcctcct 1850 cgcccgggac ccctactgtg cttggagcgg ctccagctgc aagcacgtca1900 gcctctacca gcctcagctg gccaccaggc cgtggatcca ggacatcgag 1950ggagccagcg ccaaggacct ttgcagcgcg tcttcggttg tgtccccgtc 2000 ttttgtaccaacaggggaga agccatgtga gcaagtccag ttccagccca 2050 acacagtgaa cactttggcctgcccgctcc tctccaacct ggcgacccga 2100 ctctggctac gcaacggggc ccccgtcaatgcctcggcct cctgccacgt 2150 gctacccact ggggacctgc tgctggtggg cacccaacagctgggggagt 2200 tccagtgctg gtcactagag gagggcttcc agcagctggt agccagctac2250 tgcccagagg tggtggagga cggggtggca gaccaaacag atgagggtgg 2300cagtgtaccc gtcattatca gcacatcgcg tgtgagtgca ccagctggtg 2350 gcaaggccagctggggtgca gacaggtcct actggaagga gttcctggtg 2400 atgtgcacgc tctttgtgctggccgtgctg ctcccagttt tattcttgct 2450 ctaccggcac cggaacagca tgaaagtcttcctgaagcag ggggaatgtg 2500 ccagcgtgca ccccaagacc tgccctgtgg tgctgccccctgagacccgc 2550 ccactcaacg gcctagggcc ccctagcacc ccgctcgatc accgagggta2600 ccagtccctg tcagacagcc ccccgggggc ccgagtcttc actgagtcag 2650agaagaggcc actcagcatc caagacagct tcgtggaggt atccccagtg 2700 tgcccccggccccgggtccg ccttggctcg gagatccgtg actctgtggt 2750 gtgagagctg acttccagaggacgctgccc tggcttcagg ggctgtgaat 2800 gctcggagag ggtcaactgg acctcccctccgctctgctc ttcgtggaac 2850 acgaccgtgg tgcccggccc ttgggagcct tggagccagctggcctgctg 2900 ctctccagtc aagtagcgaa gctcctacca cccagacacc caaacagccg2950 tggccccaga ggtcctggcc aaatatgggg gcctgcctag gttggtggaa 3000cagtgctcct tatgtaaact gagccctttg tttaaaaaac aattccaaat 3050 gtgaaactagaatgagaggg aagagatagc atggcatgca gcacacacgg 3100 ctgctccagt tcatggcctcccaggggtgc tggggatgca tccaaagtgg 3150 ttgtctgaga cagagttgga aaccctcaccaactggcctc ttcaccttcc 3200 acattatccc gctgccaccg gctgccctgt ctcactgcagattcaggacc 3250 agcttgggct gcgtgcgttc tgccttgcca gtcagccgag gatgtagttg3300 ttgctgccgt cgtcccacca cctcagggac cagagggcta ggttggcact 3350gcggccctca ccaggtcctg ggctcggacc caactcctgg acctttccag 3400 cctgtatcaggctgtggcca cacgagagga cagcgcgagc tcaggagaga 3450 tttcgtgaca atgtacgcctttccctcaga attcagggaa gagactgtcg 3500 cctgccttcc tccgttgttg cgtgagaacccgtgtgcccc ttcccaccat 3550 atccaccctc gctccatctt tgaactcaaa cacgaggaactaactgcacc 3600 ctggtcctct ccccagtccc cagttcaccc tccatccctc accttcctcc3650 actctaaggg atatcaacac tgcccagcac aggggccctg aatttatgtg 3700gtttttatac attttttaat aagatgcact ttatgtcatt ttttaataaa 3750 gtctgaagaattactgttta aaaaaaaaaa a 3781 2 2010 DNA Homo Sapien 2 ggaaaggctgagtctccagc tcaaggtcaa aacgtccaag gccgaaagcc 50 ctccagtttc ccctggacgccttgctcctg cttctgctac gaccttctgg 100 ggaaaacgaa tttctcattt tcttcttaaattgccatttt cgctttagga 150 gatgaatgtt ttcctttggc tgttttggca atgactctgaattaaagcga 200 tgctaacgcc tcttttcccc ctaattgtta aaagctatgg actgcaggaa250 gatggcccgc ttctcttaca gtgtgatttg gatcatggcc atttctaaag 300tctttgaact gggattagtt gccgggctgg gccatcagga atttgctcgt 350 ccatctcggggatacctggc cttcagagat gacagcattt ggccccagga 400 ggagcctgca attcggcctcggtcttccca gcgtgtgccg cccatgggga 450 tacagcacag taaggagcta aacagaacctgctgcctgaa tgggggaacc 500 tgcatgctgg ggtccttttg tgcctgccct ccctccttctacggacggaa 550 ctgtgagcac gatgtgcgca aagagaactg tgggtctgtg ccccatgaca600 cctggctgcc caagaagtgt tccctgtgta aatgctggca cggtcagctc 650cgctgctttc ctcaggcatt tctacccggc tgtgatggcc ttgtgatgga 700 tgagcacctcgtggcttcca ggactccaga actaccaccg tctgcacgta 750 ctaccacttt tatgctagttggcatctgcc tttctataca aagctactat 800 taatcgacat tgacctattt ccagaaatacaattttagat atcatgcaaa 850 tttcatgacc agtaaaggct gctgctacaa tgtcctaactgaaagatgat 900 catttgtagt tgccttaaaa taatgaatac atttccaaaa tggtctctaa950 catttcctta cagaactact tcttacttct ttgccctgcc ctctcccaaa 1000aaactacttc ttttttcaaa agaaagtcag ccatatctcc attgtgccta 1050 agtccagtgtttcttttttt tttttttttg agacggagtc tcactctgtc 1100 acccaggctg gactgcaatgacgcgatctt ggttcactgc aacctccgca 1150 tccggggttc aagccattct cctgcctcagcctcccaagt aactgggatt 1200 acaggcatgt gtcaccatgc ccagctaatt tttttgtatttttagtagag 1250 atgggggttt caccatattg gccagtctgg tctcgaactc ctgaccttgt1300 gatccactcg cctcagcctc tcgaagtgct gagattacac acgtgagcaa 1350ctgtgcaagg cctggtgttt cttgatacat gtaattctac caaggtcttc 1400 ttaatatgttcttttaaatg attgaattat atgttcagat tattggagac 1450 taattctaat gtggaccttagaatacagtt ttgagtagag ttgatcaaaa 1500 tcaattaaaa tagtctcttt aaaaggaaagaaaacatctt taaggggagg 1550 aaccagagtg ctgaaggaat ggaagtccat ctgcgtgtgtgcagggagac 1600 tgggtaggaa agaggaagca aatagaagag agaggttgaa aaacaaaatg1650 ggttacttga ttggtgatta ggtggtggta gagaagcaag taaaaaggct 1700aaatggaagg gcaagtttcc atcatctata gaaagctata taagacaaga 1750 actcccctttttttcccaaa ggcattataa aaagaatgaa gcctccttag 1800 aaaaaaaatt atacctcaatgtccccaaca agattgctta ataaattgtg 1850 tttcctccaa gctattcaat tcttttaactgttgtagaag acaaaatgtt 1900 cacaatatat ttagttgtaa accaagtgat caaactacatattgtaaagc 1950 ccatttttaa aatacattgt atatatgtgt atgcacagta aaaatggaaa2000 ctatattgaa 2010 3 549 DNA Homo Sapien 3 gccaggaggg agagccttccccaagcaaac aatccagagc agctgtgcaa 50 acaacggtgc ataaatgagg cctcctggaccatgaagcga gtcctgagct 100 gcgtcccgga gcccacggtg gtcatggctg ccagagcgctctgcatgctg 150 gggctggtcc tggccttgct gtcctccagc tctgctgagg agtacgtggg200 cctgtctgca aaccagtgtg ccgtgccagc caaggacagg gtggactgcg 250gctaccccca tgtcaccccc aaggagtgca acaaccgggg ctgctgcttt 300 gactccaggatccctggagt gccttggtgt ttcaagcccc tgcaggaagc 350 agaatgcacc ttctgaggcacctccagctg cccccggccg ggggatgcga 400 ggctcggagc acccttgccc ggctgtgattgctgccaggc actgttcatc 450 tcagcttttc tgtccctttg ctcccggcaa gcgcttctgctgaaagttca 500 tatctggagc ctgatgtctt aacgaataaa ggtcccatgc tccacccga 5494 1424 DNA Homo Sapien 4 gaccagactc gtctcaggcc agttgcagcc ttctcagccaaacgccgacc 50 aaggaaaact cactaccatg agaattgcag tgatttgctt ttgcctccta 100ggcatcacct gtgccatacc agttaaacag gctgattctg gaagttctga 150 ggaaaagcagctttacaaca aatacccaga tgctgtggcc acatggctaa 200 accctgaccc atctcagaagcagaatctcc tagccccaca gaatgctgtg 250 tcctctgaag aaaccaatga ctttaaacaagagacccttc caagtaagtc 300 caacgaaagc catgaccaca tggatgatat ggatgatgaagatgatgatg 350 accatgtgga cagccaggac tccattgact cgaacgactc tgatgatgta400 gatgacactg atgattctca ccagtctgat gagtctcacc attctgatga 450atctgatgaa ctggtcactg attttcccac ggacctgcca gcaaccgaag 500 ttttcactccagttgtcccc acagtagaca catatgatgg ccgaggtgat 550 agtgtggttt atggactgaggtcaaaatct aagaagtttc gcagacctga 600 catccagtac cctgatgcta cagacgaggacatcacctca cacatggaaa 650 gcgaggagtt gaatggtgca tacaaggcca tccccgttgcccaggacctg 700 aacgcgcctt ctgattggga cagccgtggg aaggacagtt atgaaacgag750 tcagctggat gaccagagtg ctgaaaccca cagccacaag cagtccagat 800tatataagcg gaaagccaat gatgagagca atgagcattc cgatgtgatt 850 gatagtcaggaactttccaa agtcagccgt gaattccaca gccatgaatt 900 tcacagccat gaagatatgctggttgtaga ccccaaaagt aaggaagaag 950 ataaacacct gaaatttcgt atttctcatgaattagatag tgcatcttct 1000 gaggtcaatt aaaaggagaa aaaatacaat ttctcactttgcatttagtc 1050 aaaagaaaaa atgctttata gcaaaatgaa agagaacatg aaatgcttct1100 ttctcagttt attggttgaa tgtgtatcta tttgagtctg gaaataacta 1150atgtgtttga taattagttt agtttgtggc ttcatggaaa ctccctgtaa 1200 actaaaagcttcagggttat gtctatgttc attctataga agaaatgcaa 1250 actatcactg tattttaatatttgttattc tctcatgaat agaaatttat 1300 gtagaagcaa acaaaatact tttacccacttaaaaagaga atataacatt 1350 ttatgtcact ataatctttt gttttttaag ttagtgtatattttgttgtg 1400 attatctttt tgtggtgtga ataa 1424 5 1166 DNA Homo Sapienunsure 721-761 unknown base 5 cggacgcgtg ggcggaggga agaggaccgcaaaccaaccc aggacccgct 50 cagttccacg cgcggcagcc ctccgtgcgc gcaggctcggtatgagccgc 100 acagcctaca cggtgggagc cctgcttctc ctcttgggga ccctgctgcc150 ggctgctgaa gggaaaaaga aagggtccca aggtgccatc cccccgccag 200acaaggccca gcacaatgac tcagagcaga ctcagtcgcc ccagcagcct 250 ggctccaggaaccgggggcg gggccaaggg cggggcactg ccatgcccgg 300 ggaggaggtg ctggagtccagccaagaggc cctgcatgtg acggagcgca 350 aatacctgaa gcgagactgg tgcaaaacccagccgcttaa gcagaccatc 400 cacgaggaag gctgcaacag tcgcaccatc atcaaccgcttctgttacgg 450 ccagtgcaac tctttctaca tccccaggca catccggaag gaggaaggtt500 cctttcagtc ctgctccttc tgcaagccca agaaattcac taccatgatg 550gtcacactca actgccctga actacagcca cctaccaaga agaagagagt 600 cacacgtgtgaagcagtgtc gttgcatatc catcgatttg gattaagcca 650 aatccaggtg cacccagcatgtcctaggaa tgcagcccca ggaagtccca 700 gacctaaaac aaccagattc nnnnnnnnnnnnnnnnnnnn nnnnnnnnnn 750 nnnnnnnnnn nagacttacg atgcatgtat acaaacgaatagcagataat 800 gatgactagt tcacacataa agtcctttta aggagaaaat ctaaaatgaa850 aagtggataa acagaacatt tataagtgat cagttaatgc ctaagagtga 900aagtagttct attgacattc ctcaagatat ttaatatcaa ctgcattatg 950 tattatgtctgcttaaatca tttaaaaacg gcaaagaatt atatagacta 1000 tgaggtacct tgctgtgtaggaggatgaaa ggggagttga tagtctcata 1050 aaactaattt ggcttcaagt ttcatgaatctgtaactaga atttaatttt 1100 caccccaata atgttctata tagcctttgc taaagagcaactaataaatt 1150 aaacctattc tttcaa 1166 6 2279 DNA Homo Sapien 6cggacctgaa cccctaaaag cggaaccgcc tcccgccctc gccatcgcgg 50 agctgagtcgccggcggcgg tggctgctgc cagacccgga gtttcctctt 100 tcactggatg gagctgaactttgggcggcc agagcagcac agctgtccgg 150 ggatcgctgc atgctgagct ccctcggcaagacccagcgg cggctcggga 200 tttttttggg ggggcgggga ccagccccgc gccggcaccatgttcctggc 250 gaccctgtac ttcgcgctgc cgctcttgga cttgctcctg tcggccgaag300 tgagcggcgg agaccgcctg gattgcgtga aagccagtga tcagtgcctg 350aaggagcaga gctgcagcac caagtaccgc acgctaaggc agtgcgtggc 400 gggcaaggagaccaacttca gcctggcatc cggcctggag gccaaggatg 450 agtgccgcag cgccatggaggccctgaagc agaagtcgct ctacaactgc 500 cgctgcaagc ggggtatgaa gaaggagaagaactgcctgc gcatttactg 550 gagcatgtac cagagcctgc agggaaatga tctgctggaggattccccat 600 atgaaccagt taacagcaga ttgtcagata tattccgggt ggtcccattc650 atatcagtgg agcacattcc caaagggaac aactgcctgg atgcagcgaa 700ggcctgcaac ctcgacgaca tttgcaagaa gtacaggtcg gcgtacatca 750 ccccgtgcaccaccagcgtg tccaatgatg tctgcaaccg ccgcaagtgc 800 cacaaggccc tccggcagttctttgacaag gtcccggcca agcacagcta 850 cggaatgctc ttctgctcct gccgggacatcgcctgcaca gagcggaggc 900 gacagaccat cgtgcctgtg tgctcctatg aagagagggagaagcccaac 950 tgtttgaatt tgcaggactc ctgcaagacg aattacatct gcagatctcg1000 ccttgcggat ttttttacca actgccagcc agagtcaagg tctgtcagca 1050gctgtctaaa ggaaaactac gctgactgcc tcctcgccta ctcggggctt 1100 attggcacagtcatgacccc caactacata gactccagta gcctcagtgt 1150 ggccccatgg tgtgactgcagcaacagtgg gaacgaccta gaagagtgct 1200 tgaaattttt gaatttcttc aaggacaatacatgtcttaa aaatgcaatt 1250 caagcctttg gcaatggctc cgatgtgacc gtgtggcagccagccttccc 1300 agtacagacc accactgcca ctaccaccac tgccctccgg gttaagaaca1350 agcccctggg gccagcaggg tctgagaatg aaattcccac tcatgttttg 1400ccaccgtgtg caaatttaca ggcacagaag ctgaaatcca atgtgtcggg 1450 caatacacacctctgtattt ccaatggtaa ttatgaaaaa gaaggtctcg 1500 gtgcttccag ccacataaccacaaaatcaa tggctgctcc tccaagctgt 1550 ggtctgagcc cactgctggt cctggtggtaaccgctctgt ccaccctatt 1600 atctttaaca gaaacatcat agctgcatta aaaaaatacaatatggacat 1650 gtaaaaagac aaaaaccaag ttatctgttt cctgttctct tgtatagctg1700 aaattccagt ttaggagctc agttgagaaa cagttccatt caactggaac 1750attttttttt tttcctttta agaaagcttc ttgtgatcct tcggggcttc 1800 tgtgaaaaacctgatgcagt gctccatcca aactcagaag gctttgggat 1850 atgctgtatt ttaaagggacagtttgtaac ttgggctgta aagcaaactg 1900 gggctgtgtt ttcgatgatg atgatgatcatgatgatgat catcatgatc 1950 atgatgatga tcatcatgat catgatgatg attttaacagttttacttct 2000 ggcctttcct agctagagaa ggagttaata tttctaaggt aactcccata2050 tctcctttaa tgacattgat ttctaatgat ataaatttca gcctacattg 2100atgccaagct tttttgccac aaagaagatt cttaccaaga gtgggctttg 2150 tggaaacagctggtactgat gttcaccttt atatatgtac tagcattttc 2200 cacgctgatg tttatgtactgtaaacagtt ctgcactctt gtacaaaaga 2250 aaaaacacct gtcacatcca aatataaaa2279 7 562 DNA Homo Sapien 7 atgcagcacc gaggcttcct cctcctcacc ctcctcgccctgctggcgct 50 cacctccgcg gtcgccaaaa agaaagataa ggtgaagaag ggcggcccgg 100ggagcgagtg cgctgagtgg gcctgggggc cctgcacccc cagcagcaag 150 gattgcggcgtgggtttccg cgagggcacc tgcggggccc agacccagcg 200 catccggtgc agggtgccctgcaactggaa gaaggagttt ggagccgact 250 gcaagtacaa gtttgagaac tggggtgcgtgtgatggggg cacaggcacc 300 aaagtccgcc aaggcaccct gaagaaggcg cgctacaatgctcagtgcca 350 ggagaccatc cgcgtcacca agccctgcac ccccaagacc aaagcaaagg400 ccaaagccaa gaaagggaag ggaaaggact agacgccaag cctggatgcc 450aaggagcccc tggtgtcaca tggggcctgg cccacgccct ccctctccca 500 ggcccgagatgtgacccacc agtgccttct gtctgctcgt tagctttaat 550 caatcatgcc cc 562 8 1524DNA Homo Sapien 8 gcggcagcag cgcgggcccc agcagcctcg gcagccacag ccgctgcagc50 cggggcagcc tccgctgctg tcgcctcctc tgatgcgctt gccctctccc 100 ggccccgggactccgggaga atgtgggtcc taggcatcgc ggcaactttt 150 tgcggattgt tcttgcttccaggctttgcg ctgcaaatcc agtgctacca 200 gtgtgaagaa ttccagctga acaacgactgctcctccccc gagttcattg 250 tgaattgcac ggtgaacgtt caagacatgt gtcagaaagaagtgatggag 300 caaagtgccg ggatcatgta ccgcaagtcc tgtgcatcat cagcggcctg350 tctcatcgcc tctgccgggt accagtcctt ctgctcccca gggaaactga 400actcagtttg catcagctgc tgcaacaccc ctctttgtaa cgggccaagg 450 cccaagaaaaggggaagttc tgcctcggcc ctcaggccag ggctccgcac 500 caccatcctg ttcctcaaattagccctctt ctcggcacac tgctgaagct 550 gaaggagatg ccaccccctc ctgcattgttcttccagccc tcgcccccaa 600 ccccccacct ccctgagtga gtttcttctg ggtgtccttttattctgggt 650 agggagcggg agtccgtgtt ctcttttgtt cctgtgcaaa taatgaaaga700 gctcggtaaa gcattctgaa taaattcagc ctgactgaat tttcagtatg 750tacttgaagg aaggaggtgg agtgaaagtt cacccccatg tctgtgtaac 800 cggagtcaaggccaggctgg cagagtcagt ccttagaagt cactgaggtg 850 ggcatctgcc ttttgtaaagcctccagtgt ccattccatc cctgatgggg 900 gcatagtttg agactgcaga gtgagagtgacgttttctta gggctggagg 950 gccagttccc actcaaggct ccctcgcttg acattcaaacttcatgctcc 1000 tgaaaaccat tctctgcagc agaattggct ggtttcgcgc ctgagttggg1050 ctctagtgac tcgagactca atgactggga cttagactgg ggctcggcct 1100cgctctgaaa agtgcttaag aaaatcttct cagttctcct tgcagaggac 1150 tggcgccgggacgcgaagag caacgggcgc tgcacaaagc gggcgctgtc 1200 ggtggtggag tgcgcatgtacgcgcaggcg cttctcgtgg ttggcgtgct 1250 gcagcgacag gcggcagcac agcacctgcacgaacacccg ccgaaactgc 1300 tgcgaggaca ccgtgtacag gagcgggttg atgaccgagctgaggtagaa 1350 aaacgtctcc gagaagggga ggaggatcat gtacgcccgg aagtaggacc1400 tcgtccagtc gtgcttgggt ttggccgcag ccatgatcct ccgaatctgg 1450ttgggcatcc agcatacggc caatgtcaca acaatcagcc ctgggcagac 1500 acgagcaggagggagagaca gaga 1524 9 1253 DNA Homo Sapien 9 caccctccgt ggcaaggcgaggccccgggg gcgggccggg gtcaccacgc 50 ctgccccagg gaaccgcaca gacggtactcacccttcttg cgatgatgtg 100 agatgataaa atgcctacat gatgagatga agtgagatgaaaaacatagg 150 ccttgtgatg gaatgggaaa ttccagagat aatttgcacg tgcgctaagc200 tgcggctacc cccgcaagca accttccaag tccttcgtgg caatggtgct 250tccgtgggga ccgtgctcat gttccgctgc ccctccaacc accagatggt 300 ggggtctgggctcctcacct gcacctggaa ggggagcatc gctgagtggt 350 cttcagggtc cccagtgtgcaaactggtgc caccacacga gacctttggc 400 ttcaaggtgg ccgtgatcgc ctccattgtgagctgtgcca tcatcctgct 450 catgtccatg gccttcctca cctgctgcct cctcaagtgcgtgaagaaga 500 gcaagcggcg gcgctccaac aggtcagccc agctgtggtc ccagctgaaa550 gatgaggact tggagacggt gcaggccgca taccttggcc tcaagcactt 600caacaaaccc gtgagcgggc ccagccaggc gcacgacaac cacagcttca 650 ccacagaccatggtgagagc accagcaagc tggccagtgt gacccgcagc 700 gtggacaagg accctgggatccccagagct ctaagcctca gtggctcctc 750 cagctcaccc caagcccagg tgatggtgcacatggcaaac cccagacagc 800 ccctgcctgc ctctgggctg gccacaggaa tgccacaacagcccgcagca 850 tatgccctag ggtgaccacg cagtgaggct ggtgcccatg ctccacactg900 ggaggccagg ctgaccccac cagccagtca gctacaactc cacatcaact 950ccacatgcgc ccagctcgag actgatgagt ggaatcagct tccaggtgta 1000 gggaccccttgaggggccga gctgacatcc aaggctgagg accccagtgg 1050 ggagtgttct gttccggcatatcctggccg taacgatttt tatagttatg 1100 gactacttga aaccactact gagggtaatttactagctgt ggcctcccac 1150 taactagcat tcctttaaag agactgggaa atgttttaagcaaatctagt 1200 tttgtataat aaaataagaa aatagcaata aacttctttt cagcaactac1250 aaa 1253 10 5542 DNA Homo Sapien 10 ctgactgcac tggtgatggtccctggcaat ccaacctggc accatcgcag 50 ttggagtact atgcatcttc accagatgaaaaggctctag tagaagctgc 100 tgcaaggatt ggtattgtgt ttattggcaa ttctgaagaaactatggagg 150 ttaaaactct tggaaaactg gaacggtaca aactgcttca tattctggaa200 tttgattcag atcgtaggag aatgagtgta attgttcagg caccttcagg 250tgagaagtta ttatttgcta aaggagctga gtcatcaatt ctccctaaat 300 gtataggtggagaaatagaa aaaaccagaa ttcatgtaga tgaatttgct 350 ttgaaagggc taagaactctgtgtatagca tatagaaaat ttacatcaaa 400 agagtatgag gaaatagata aacgcatatttgaagccagg actgccttgc 450 agcagcggga agagaaattg gcagctgttt tccagttcatagagaaagac 500 ctgatattac ttggagccac agcagtagaa gacagactac aagataaagt550 tcgagaaact attgaagcat tgagaatggc tggtatcaaa gtatgggtac 600ttactgggga taaacatgaa acagctgtta gtgtgagttt atcatgtggc 650 cattttcatagaaccatgaa catccttgaa cttataaacc agaaatcaga 700 cagcgagtgt gctgaacaattgaggcagct tgccagaaga attacagagg 750 atcatgtgat tcagcatggg ctggtagtggatgggaccag cctatctctt 800 gcactcaggg agcatgaaaa actatttatg gaagtttgcagaaattgttc 850 agctgtatta tgctgtcgta tggctccact gcagaaagca aaagtaataa900 gactaataaa aatatcacct gagaaaccta taacattggc tgttggtgat 950ggtgctaatg acgtaagcat gatacaagaa gcccatgttg gcataggaat 1000 catgggtaaagaaggaagac aggctgcaag aaacagtgac tatgcaatag 1050 ccagatttaa gttcctctccaaattgcttt ttgttcatgg tcatttttat 1100 tatattagaa tagctaccct tgtacagtattttttttata agaatgtgtg 1150 ctttatcaca ccccagtttt tatatcagtt ctactgtttgttttctcagc 1200 aaacattgta tgacagcgtg tacctgactt tatacaatat ttgttttact1250 tccctaccta ttctgatata tagtcttttg gaacagcatg tagaccctca 1300tgtgttacaa aataagccca ccctttatcg agacattagt aaaaaccgcc 1350 tcttaagtattaaaacattt ctttattgga ccatcctggg cttcagtcat 1400 gcctttattt tcttttttggatcctattta ctaataggga aagatacatc 1450 tctgcttgga aatggccaga tgtttggaaactggacattt ggcactttgg 1500 tcttcacagt catggttatt acagtcacag taaagatggctctggaaact 1550 catttttgga cttggatcaa ccatctcgtt acctggggat ctattatatt1600 ttattttgta ttttccttgt tttatggagg gattctctgg ccatttttgg 1650gctcccagaa tatgtatttt gtgtttattc agctcctgtc aagtggttct 1700 gcttggtttgccataatcct catggttgtt acatgtctat ttcttgatat 1750 cataaagaag gtctttgaccgacacctcca ccctacaagt actgaaaagg 1800 cacagcttac tgaaacaaat gcaggtatcaagtgcttgga ctccatgtgc 1850 tgtttcccgg aaggagaagc agcgtgtgca tctgttggaagaatgctgga 1900 acgagttata ggaagatgta gtccaaccca catcagcaga tcatggagtg1950 catcggatcc tttctatacc aacgacagga gcatcttgac tctctccaca 2000atggactcat ctacttgtta aaggggcagt agtactttgt gggagccagt 2050 tcacctcctttcctaaaatt cagtgtgatc accctgttaa tggccacact 2100 agctctgaaa ttaatttccaaaatctttgt agtagttcat acccactcag 2150 agttataatg gcaaacaaac agaaagcattagtacaagcc cctcccaaca 2200 cccttaattt gaatctgaac atgttaaaat ttgagaataaagagacattt 2250 ttcatctctt tgtctggttt gtcccttgtg cttatgggac tcctaatggc2300 atttcagtct gttgctgagg ccattatatt ttaatataaa tgtagaaaaa 2350agagagaaat cttagtaaag agtatttttt agtattagct tgattattga 2400 ctcttctatttaaatctgct tctgtaaatt atgctgaaag tttgccttga 2450 gaactctatt tttttattagagttatattt aaagcttttc atgggaaaag 2500 ttaatgtgaa tactgaggaa ttttggtccctcagtgacct gtgttgttaa 2550 ttcattaatg cattctgagt tcacagagca aattaggagaatcatttcca 2600 accattattt actgcagtat ggggagtaaa tttataccaa ttcctctaac2650 tgtactgtaa cacagcctgt aaagttagcc atataaatgc aagggtatat 2700catatataca aatcaggaat caggtccgtt caccgaactt caaattgatg 2750 tttactaatatttttgtgac agagtataaa gaccctatag tgggtaaatt 2800 agatactatt agcatattattaatttaatg tctttatcat tggatctttt 2850 gcatgcttta atctggttaa catatttaaatttgcttttt ttctctttac 2900 ctgaaggctc tgtgtatagt atttcatgac atcgttgtacagtttaacta 2950 tcaataaaaa gtttggacag tatttaaata ttgcaaatat gtttaattat3000 acaaatcaga atagtatggg taattaaatg aatacaaaaa gaagagcctc 3050tttctgcagc cgacttagac atgctcttcc ctttctataa gctagatttt 3100 agaataaagggtttcagtta ataatcttat tttcaggtta tgtcatctaa 3150 cttatagcaa actaccacaatacagtgagt tctgccagtg tcccagtaca 3200 aggcatattt caggtgtggc tgtggaatgtaaaaatgctc aacttgtatc 3250 aggtaatgtt agcaataaat taaatgctaa gaatgattaatcgggtacat 3300 gttactgtaa ttaactcatt gcacttcaaa acctaacttc catcctgaat3350 ttatcaagta gttcagtatt gtcatttgtt tttgttttat tgaaaagtaa 3400tgttgtctta agatttagaa gtgattatta gcttgagaac tattacccag 3450 ctctaagcaaataatgattg tatacatatt aagataatgg ttaaatgcgg 3500 ttttaccaag ttttcccttgaaaatgtaat tcctttatgg agatttattg 3550 tgcagcccta agcttccttc ccatttcatgaatataaggc ttctagaatt 3600 ggactggcag gggaaagaat ggtagagaca gaaattaagactttatcctt 3650 gtttgcttgt aaactattat tttcttgcta atgtaacatt tgtctgttcc3700 agtgatgtaa ggatattaag ttattaagct aaatattaat tttcaaaaat 3750agtccttctt taacttagat atttcatagc tggatttagg aagatctgtt 3800 attctggaagtactaaaaag aataatacaa cgtacaatgt ctgcattcac 3850 taattcatgt tccagaagaggaaataatga agatatactc agtagagtac 3900 taggtgggag gatatggaaa tttgctcataaaatctctta taaaacgtgc 3950 atataacaaa atgacaccca gtaggcctgc attacatttacatgaccgtg 4000 tttatttgcc atcaaataaa ctgagtactg acaccagaca aagactccaa4050 agtcataaaa tagcctatga ccaactgcag caagacagga ggtcagctcg 4100cctataatgg tgcttaaagt gtgattgatg taattttctg tactcaccat 4150 ttgaagttagttaaggagaa ctttattttt ttaaaaaaag taaatggcaa 4200 ccactagtgt gctcatcctgaactgttact ccaaatccac tccgttttta 4250 aagcaaaatt atcttgtgat tttaagaaaagagttttcta tttatttaag 4300 aaagtaacaa tgcagtctgc aagctttcag tagttttctagtgctatatt 4350 catcctgtaa aactcttact acgtaaccag taatcacaag gaaagtgtcc4400 cctttgcata tttctttaaa attctttctt tggaaagtat gatgttgata 4450attaacttac ccttatctgc caaaaccaga gcaaaatgct aaatacgtta 4500 ttgctaatcagtggtctcaa atcgatttgc ctccctttgc ctcgtctgag 4550 ggctgtaagc ctgaagatagtggcaagcac caagtcagtt tccaaaattg 4600 cccctcagct gctttaagtg actcagcaccctgcctcagc ttcagcaggc 4650 gtaggctcac cctgggcgga gcaaagtatg ggccagggagaactacagct 4700 acgaagacct gctgtcgagt tgagaaaagg ggagaattta tggtctgaat4750 tttctaactg tcctctttct tgggtctaaa gctcataata cacaaaggct 4800tccagacctg agccacaccc aggccctatc ctgaacagga gactaaacag 4850 aggcaaatcaaccctaggaa atacttgcat tctgccctac ggttagtacc 4900 aggactgagg tcatttctactggaaaagat tgtgagattg aacttatctg 4950 atcgcttgag actcctaata ggcaggagtcaaggccacta gaaaattgac 5000 agttaagagc caaaagtttt taaaatatgc tactctgaaaaatctcgtga 5050 aggctgtagg aaaagggaga atcttccatg ttggtgtttt tcctgtaaag5100 atcagtttgg ggtatgatat aagcaggtat taataaaaat aacacaccaa 5150agagttacgt aaaacatgtt ttattaattt tggtccccac gtacagacat 5200 tttatttctattttgaaatg agttatctat tttcataaaa gtaaaacact 5250 attaaagtgc tgttttatgtgaaataactt gaatgttgtt cctataaaaa 5300 atagatcata actcatgata tgtttgtaatcatggtaatt tagattttta 5350 tgaggaatga gtatctggaa atattgtagc aatacttggtttaaaatttt 5400 ggacctgaga cactgtggct gtctaatgta atcctttaaa aattctctgc5450 attgtcagta aatgtagtat attattgtac agctactcat aattttttaa 5500agtttatgaa gttatattta tcaaataaaa actttcctat at 5542 11 6155 DNA HomoSapien 11 atgtgggaag aagaagacat tgctattctg ttcaataaag aaccaggaaa 50aacagagaat attgaaaata atctaagttc caaccataga agaagctgca 100 gaagaagtgaagaaagtgat gatgatttgg attttgatat tggtttagaa 150 aacacaggag gagaccctcaaattctgaga tttatttcag acttccttgc 200 ttttttggtt ctctacaatt tcatcattccaatttcatta tatgtgacag 250 tcgaaatgca gaaatttctt ggatcatttt ttattggctgggatcttgat 300 ctgtatcatg aagaatcaga tcagaaagct caagtcaata cttccgatct350 gaatgaagag cttggacagg tagagtacgt gtttacagat aaaactggta 400cactgacaga aaatgagatg cagtttcggg aatgttcaat taatggcatg 450 aaataccaagaaattaatgg tagacttgta cccgaaggac caacaccaga 500 ctcttcagaa ggaaacttatcttatcttag tagtttatcc catcttaaca 550 acttatccca tcttacaacc agttcctctttcagaaccag tcctgaaaat 600 gaaactgaac taattaaaga acatgatctc ttctttaaagcagtcagtct 650 ctgtcacact gtacagatta gcaatgttca aactgactgc actggtgatg700 gtccctggca atccaacctg gcaccatcgc agttggagta ctatgcatct 750tcaccagatg aaaaggctct agtagaagct gctgcaaggt acaaactgct 800 tcatattctggaatttgatt cagatcgtag gagaatgagt gtaattgttc 850 aggcaccttc aggtgagaagttattatttg ctaaaggagc tgagtcatca 900 attctcccta aatgtatagg tggagaaatagaaaaaacca gaattcatgt 950 agatgaattt gctttgaaag ggctaagaac tctgtgtatagcatatagaa 1000 aatttacatc aaaagagtat gaggaaatag ataaacgcat atttgaagcc1050 aggactgcct tgcagcagcg ggaagagaaa ttggcagctg ttttccagtt 1100catagagaaa gacctgatat tacttggagc cacagcagta gaagacagac 1150 tacaagataaagttcgagaa actattgaag cattgagaat ggctggtatc 1200 aaagtatggg tacttactggggataaacat gaaacagctg ttagtgtgag 1250 tttatcatgt ggccattttc atagaaccatgaacatcctt gaacttataa 1300 accagaaatc agacagcgag tgtgctgaac aattgaggcagcttgccaga 1350 agaattacag aggatcatgt gattcagcat gggctggtag tggatgggac1400 cagcctatct cttgcactca gggagcatga aaaactattt atggaagttt 1450gcagaaattg ttcagctgta ttatgctgtc gtatggctcc actgcagaaa 1500 gcaaaagtaataagactaat aaaaatatca cctgagaaac ctataacatt 1550 ggctgttggt gatggtgctaatgacgtaag catgatacaa gaagcccatg 1600 ttggcatagg aatcatgggt aaagaaggaagacaggctgc aagaaacagt 1650 gactatgcaa tagccagatt taagttcctc tccaaattgctttttgttca 1700 tggtcatttt tattatatta gaatagctac ccttgtacag tatttttttt1750 ataagaatgt gtgctttatc acaccccagt ttttatatca gttctactgt 1800ttgttttctc agcaaacatt gtatgacagc gtgtacctga ctttatacaa 1850 tatttgttttacttccctac ctattctgat atatagtctt ttggaacagc 1900 atgtagaccc tcatgtgttacaaaataagc ccacccttta tcgagacatt 1950 agtaaaaacc gcctcttaag tattaaaacatttctttatt ggaccatcct 2000 gggcttcagt catgccttta ttttcttttt tggatcctatttactaatag 2050 ggaaagatac atctctgctt ggaaatggcc agatgtttgg aaactggaca2100 tttggcactt tggtcttcac agtcatggtt attacagtca cagtaaagat 2150ggctctggaa actcattttt ggacttggat caaccatctc gttacctggg 2200 gatctattatattttatttt gtattttcct tgttttatgg agggattctc 2250 tggccatttt tgggctcccagaatatgtat tttgtgttta ttcagctcct 2300 gtcaagtggt tctgcttggt ttgccataatcctcatggtt gttacatgtc 2350 tatttcttga tatcataaag aaggtctttg accgacacctccaccctaca 2400 agtactgaaa aggcacagct tactgaaaca aatgcaggta tcaagtgctt2450 ggactccatg tgctgtttcc cggaaggaga agcagcgtgt gcatctgttg 2500gaagaatgct ggaacgagtt ataggaagat gtagtccaac ccacatcagc 2550 agatcatggagtgcatcgga tcctttctat accaacgaca ggagcatctt 2600 gactctctcc acaatggactcatctacttg ttaaaggggc agtagtactt 2650 tgtgggagcc agttcacctc ctttcctaaaattcagtgtg atcaccctgt 2700 taatggccac actagctctg aaattaattt ccaaaatctttgtagtagtt 2750 catacccact cagagttata atggcaaaca aacagaaagc attagtacaa2800 gcccctccca acacccttaa tttgaatctg aacatgttaa aatttgagaa 2850taaagagaca tttttcatct ctttgtctgg tttgtccctt gtgcttatgg 2900 gactcctaatggcatttcag tctgttgctg aggccattat attttaatat 2950 aaatgtagaa aaaagagagaaatcttagta aagagtattt tttagtatta 3000 gcttgattat tgactcttct atttaaatctgcttctgtaa attatgctga 3050 aagtttgcct tgagaactct atttttttat tagagttatatttaaagctt 3100 ttcatgggaa aagttaatgt gaatactgag gaattttggt ccctcagtga3150 cctgtgttgt taattcatta atgcattctg agttcacaga gcaaattagg 3200agaatcattt ccaaccatta tttactgcag tatggggagt aaatttatac 3250 caattcctctaactgtactg taacacagcc tgtaaagtta gccatataaa 3300 tgcaagggta tatcatatatacaaatcagg aatcaggtcc gttcaccgaa 3350 cttcaaattg atgtttacta atatttttgtgacagagtat aaagacccta 3400 tagtgggtaa attagatact attagcatat tattaatttaatgtctttat 3450 cattggatct tttgcatgct ttaatctggt taacatattt aaatttgctt3500 tttttctctt tacctgaagg ctctgtgtat agtatttcat gacatcgttg 3550tacagtttaa ctatcaataa aaagtttgga cagtatttaa atattgcaaa 3600 tatgtttaattatacaaatc agaatagtat gggtaattaa atgaatacaa 3650 aaagaagagc ctctttctgcagccgactta gacatgctct tccctttcta 3700 taagctagat tttagaataa agggtttcagttaataatct tattttcagg 3750 ttatgtcatc taacttatag caaactacca caatacagtgagttctgcca 3800 gtgtcccagt acaaggcata tttcaggtgt ggctgtggaa tgtaaaaatg3850 ctcaacttgt atcaggtaat gttagcaata aattaaatgc taagaatgat 3900taatcgggta catgttactg taattaactc attgcacttc aaaacctaac 3950 ttccatcctgaatttatcaa gtagttcagt attgtcattt gtttttgttt 4000 tattgaaaag taatgttgtcttaagattta gaagtgatta ttagcttgag 4050 aactattacc cagctctaag caaataatgattgtatacat attaagataa 4100 tggttaaatg cggttttacc aagttttccc ttgaaaatgtaattccttta 4150 tggagattta ttgtgcagcc ctaagcttcc ttcccatttc atgaatataa4200 ggcttctaga attggactgg caggggaaag aatggtagag acagaaatta 4250agactttatc cttgtttgct tgtaaactat tattttcttg ctaatgtaac 4300 atttgtctgttccagtgatg taaggatatt aagttattaa gctaaatatt 4350 aattttcaaa aatagtccttctttaactta gatatttcat agctggattt 4400 aggaagatct gttattctgg aagtactaaaaagaataata caacgtacaa 4450 tgtctgcatt cactaattca tgttccagaa gaggaaataatgaagatata 4500 ctcagtagag tactaggtgg gaggatatgg aaatttgctc ataaaatctc4550 ttataaaacg tgcatataac aaaatgacac ccagtaggcc tgcattacat 4600ttacatgacc gtgtttattt gccatcaaat aaactgagta ctgacaccag 4650 acaaagactccaaagtcata aaatagccta tgaccaactg cagcaagaca 4700 ggaggtcagc tcgcctataatggtgcttaa agtgtgattg atgtaatttt 4750 ctgtactcac catttgaagt tagttaaggagaactttatt tttttaaaaa 4800 aagtaaatgg caaccactag tgtgctcatc ctgaactgttactccaaatc 4850 cactccgttt ttaaagcaaa attatcttgt gattttaaga aaagagtttt4900 ctatttattt aagaaagtaa caatgcagtc tgcaagcttt cagtagtttt 4950ctagtgctat attcatcctg taaaactctt actacgtaac cagtaatcac 5000 aaggaaagtgtcccctttgc atatttcttt aaaattcttt ctttggaaag 5050 tatgatgttg ataattaacttacccttatc tgccaaaacc agagcaaaat 5100 gctaaatacg ttattgctaa tcagtggtctcaaatcgatt tgcctccctt 5150 tgcctcgtct gagggctgta agcctgaaga tagtggcaagcaccaagtca 5200 gtttccaaaa ttgcccctca gctgctttaa gtgactcagc accctgcctc5250 agcttcagca ggcgtaggct caccctgggc ggagcaaagt atgggccagg 5300gagaactaca gctacgaaga cctgctgtcg agttgagaaa aggggagaat 5350 ttatggtctgaattttctaa ctgtcctctt tcttgggtct aaagctcata 5400 atacacaaag gcttccagacctgagccaca cccaggccct atcctgaaca 5450 ggagactaaa cagaggcaaa tcaaccctaggaaatacttg cattctgccc 5500 tacggttagt accaggactg aggtcatttc tactggaaaagattgtgaga 5550 ttgaacttat ctgatcgctt gagactccta ataggcagga gtcaaggcca5600 ctagaaaatt gacagttaag agccaaaagt ttttaaaata tgctactctg 5650aaaaatctcg tgaaggctgt aggaaaaggg agaatcttcc atgttggtgt 5700 ttttcctgtaaagatcagtt tggggtatga tataagcagg tattaataaa 5750 aataacacac caaagagttacgtaaaacat gttttattaa ttttggtccc 5800 cacgtacaga cattttattt ctattttgaaatgagttatc tattttcata 5850 aaagtaaaac actattaaag tgctgtttta tgtgaaataacttgaatgtt 5900 gttcctataa aaaatagatc ataactcatg atatgtttgt aatcatggta5950 atttagattt ttatgaggaa tgagtatctg gaaatattgt agcaatactt 6000ggtttaaaat tttggacctg agacactgtg gctgtctaat gtaatccttt 6050 aaaaattctctgcattgtca gtaaatgtag tatattattg tacagctact 6100 cataattttt taaagtttatgaagttatat ttatcaaata aaaactttcc 6150 tatat 6155 12 1372 DNA Homo Sapien12 gcacgagggc gcttttgtct ccggtgagtt ttgtggcggg aagcttctgc 50 gctggtgcttagtaaccgac tttcctccgg actcctgcac gacctgctcc 100 tacagccggc gatccactcccggctgttcc cccggagggt ccagaggcct 150 ttcagaagga gaaggcagct ctgtttctctgcagaggagt agggtccttt 200 cagccatgaa gcatgtgttg aacctctacc tgttaggtgtggtactgacc 250 ctactctcca tcttcgttag agtgatggag tccctagaag gcttactaga300 gagcccatcg cctgggacct cctggaccac cagaagccaa ctagccaaca 350cagagcccac caagggcctt ccagaccatc catccagaag catgtgataa 400 gacctccttccatactggcc atattttgga acactgacct agacatgtcc 450 agatgggagt cccattcctagcagacaagc tgagcaccgt tgtaaccaga 500 gaactattac taggccttga agaacctgtctaactggatg ctcattgcct 550 gggcaaggcc tgtttaggcc ggttgcggtg gctcatgcctgtaatcctag 600 cactttggga ggctgaggtg ggtggatcac ctgaggtcag gagttcgaga650 ccagcctcgc caacatggcg aaaccccatc tctactaaaa atacaaaagt 700tagctgggtg tggtggcaga ggcctgtaat cccagttcct tgggaggctg 750 aggcgggagaattgcttgaa cccggggacg gaggttgcag tgaaccgaga 800 tcgcactgct gtacccagcctgggccacag tgcaagactc catctcaaaa 850 aaaaaaagaa aagaaaaagc ctgtttaatgcacaggtgtg agtggattgc 900 ttatggctat gagataggtt gatctcgccc ttaccccggggtctggtgta 950 tgctgtgctt tcctcagcag tatggctctg acatctctta gatgtcccaa1000 cttcagctgt tgggagatgg tgatattttc aaccctactt cctaaacatc 1050tgtctggggt tcctttagtc ttgaatgtct tatgctcaat tatttggtgt 1100 tgagcctctcttccacaaga gctcctccat gtttggatag cagttgaaga 1150 ggttgtgtgg gtgggctgttgggagtgagg atggagtgtt cagtgcccat 1200 ttctcatttt acattttaaa gtcgttcctccaacatagtg tgtattggtc 1250 tgaagggggt ggtgggatgc caaagcctgc tcaagttatggacattgtgg 1300 ccaccatgtg gcttaaatga ttttttctaa ctaataaagt ggaatatata1350 tttcaaaaaa aaaaaaaaaa aa 1372 13 770 DNA Homo Sapien unsure 45,611, 715 unknown base 13 atacgactca ctatagggcg aattgggtac cgggccccccctcgngtcga 50 cggtatcgat aagcttgata tcgaattcgg ccacactggc cggatcctct 100agagatccct cgacctcgac ccacgcgtcc gcccacgcgt ccgatgtgcc 150 tctgggcaaagaagcagagc taacgaggaa agggatttaa agagtttttc 200 ttgggtgttt gtcaaacttttattccctgt ctgtgtgcag aggggattca 250 acttcaattt ttctgcagtg gctctgagtccagcccctta cttaaagatc 300 tggaaagcat gaagactggg ctttttttcc tatgtctcttgggaactgca 350 gctgcaatcc cgacaaatgc aagattatta tctgatcatt ccaaaccaac400 tgctgaaacg gtagcacccg acaacactgc aatccccagt ttaagggctg 450aagatgaaga aaatgaaaaa gaaacagcag tatccacaga agacgattcc 500 caccataaggctgaaaaatc atcagtacta aagtcaaaag aggaaagcca 550 tgaacagtca gcagaacagggcaagagttc tagccaagag ctgggattga 600 aggatcaaga ngacagtgat ggtgacttaagtgtgaattt ggagtatgca 650 ccaactgaag gtacattgga cataaaagaa gatatgagtgagcctcagga 700 gaaaaactct caganacact gattttttgg ctcctggggt agttccttcc750 agattctacc acagaagttt 770 14 1187 DNA Homo Sapien 14 cgcgggccatggctccctgg gcggaggccg agcactcggc gctgaacccg 50 ctgcgcgcgg tgtggctcacgctgaccgcc gccttcctgc tgaccctact 100 gctgcagctc ctgccgcccg gcctgctcccgggctgcgcg atcttccagg 150 acctgatccg ctatgggaaa accaagtgtg gggagccgtcgcgccccgcc 200 gcctgccgag cctttgatgt ccccaagaga tatttttccc acttttatat250 catctcagtg ctgtggaatg gcttcctgct ttggtgcctt actcaatctc 300tgttcctggg agcacctttt ccaagctggc ttcatggttt gctcagaatt 350 ctcggggcggcacagttcca gggaggggag ctggcactgt ctgcattctt 400 agtgctagta tttctgtggctgcacagctt acgaagactc ttcgagtgcc 450 tctacgtcag tgtcttctcc aatgtcatgattcacgtcgt gcagtactgt 500 tttggacttg tctattatgt ccttgttggc ctaactgtgctgagccaagt 550 gccaatggat ggcaggaatg cctacataac agggaaaaat ctattgatgc600 aagcacggtg gttccatatt cttgggatga tgatgttcat ctggtcatct 650gcccatcagt ataagtgcca tgttattctc ggcaatctca ggaaaaataa 700 agcaggagtggtcattcact gtaaccacag gatcccattt ggagactggt 750 ttgaatatgt ttcttcccctaactacttag cagagctgat gatctacgtt 800 tccatggccg tcacctttgg gttccacaacttaacttggt ggctagtggt 850 gacaaatgtc ttctttaatc aggccctgtc tgcctttctcagccaccaat 900 tctacaaaag caaatttgtc tcttacccga agcataggaa agctttccta950 ccatttttgt tttaagttaa cctcagtcat gaagaatgca aaccaggtga 1000tggtttcaat gcctaaggac agtgaagtct ggagcccaaa gtacagtttc 1050 agcaaagctgtttgaaactc tccattccat ttctataccc cacaagtttt 1100 cactgaatga gcatggcagtgccactcaat aaaatgaatc tccaaagtat 1150 cttcaaagaa taaatactaa tggcaaaaaaaaaaaaa 1187 15 1840 DNA Homo Sapien 15 tccacacaca caaaaaacct gcgcgtgaggggggaggaaa agcagggcct 50 ttaaaaaggc aatcacaaca acttttgctg ccaggatgcccttgctttgg 100 ctgagaggat ttctgttggc aagttgctgg attatagtga ggagttcccc150 caccccagga tccgaggggc acagcgcggc ccccgactgt ccgtcctgtg 200cgctggccgc cctcccaaag gatgtaccca actctcagcc agagatggtg 250 gaggccgtcaagaagcacat tttaaacatg ctgcacttga agaagagacc 300 cgatgtcacc cagccggtacccaaggcggc gcttctgaac gcgatcagaa 350 agcttcatgt gggcaaagtc ggggagaacgggtatgtgga gatagaggat 400 gacattggaa ggagggcaga aatgaatgaa cttatggagcagacctcgga 450 gatcatcacg tttgccgagt caggaacagc caggaagacg ctgcacttcg500 agatttccaa ggaaggcagt gacctgtcag tggtggagcg tgcagaagtc 550tggctcttcc taaaagtccc caaggccaac aggaccagga ccaaagtcac 600 catccgcctcttccagcagc agaagcaccc gcagggcagc ttggacacag 650 gggaagaggc cgaggaagtgggcttaaagg gggagaggag tgaactgttg 700 ctctctgaaa aagtagtaga cgctcggaagagcacctggc atgtcttccc 750 tgtctccagc agcatccagc ggttgctgga ccagggcaagagctccctgg 800 acgttcggat tgcctgtgag cagtgccagg agagtggcgc cagcttggtt850 ctcctgggca agaagaagaa gaaagaagag gagggggaag ggaaaaagaa 900gggcggaggt gaaggtgggg caggagcaga tgaggaaaag gagcagtcgc 950 acagacctttcctcatgctg caggcccggc agtctgaaga ccaccctcat 1000 cgccggcgtc ggcggggcttggagtgtgat ggcaaggtca acatctgctg 1050 taagaaacag ttctttgtca gtttcaaggacatcggctgg aatgactgga 1100 tcattgctcc ctctggctat catgccaact actgcgagggtgagtgcccg 1150 agccatatag caggcacgtc cgggtcctca ctgtccttcc actcaacagt1200 catcaaccac taccgcatgc ggggccatag cccctttgcc aacctcaaat 1250cgtgctgtgt gcccaccaag ctgagaccca tgtccatgtt gtactatgat 1300 gatggtcaaaacatcatcaa aaaggacatt cagaacatga tcgtggagga 1350 gtgtgggtgc tcatagagttgcccagccca gggggaaagg gagcaagagt 1400 tgtccagaga agacagtggc aaaatgaagaaatttttaag gtttctgagt 1450 taaccagaaa aatagaaatt aaaaacaaaa caaaacaaaaaaaaaaacaa 1500 aaaaaaacaa aagtaaatta aaaacaaacc tgatgaaaca gatgaaacag1550 atgaaggaag atgtggaaat cttagcctgc cttagccagg gctcagagat 1600gaagcagtga agagacagat tgggagggaa agggagaatg gtgtaccctt 1650 tatttcttctgaaatcacac tgatgacatc agttgtttaa acggggtatt 1700 gtcctttccc cccttgaggttcccttgtga gcttgaatca accaatctga 1750 tctgcagtag tgtggactag aacaacccaaatagcatcta gaaagccatg 1800 agtttgaaag ggcccatcac aggcactttc ctagcctaat1840 16 1771 DNA Homo Sapien 16 gcggagaagc cgggagcgcg gggctcagtcggggggcggc ggcggcggcg 50 gctccgggga tggcggcggc tccgctgctg ctgctgctgctgctcgtgcc 100 cgtgccgctg ctgccgctgc tggcccaagg gcccggaggg gcgctgggaa150 accggcatgc ggtgtactgg aacagctcca accagcacct gcggcgagag 200ggctacaccg tgcaggtgaa cgtgaacgac tatctggata tttactgccc 250 gcactacaacagctcggggg tgggccccgg ggcgggaccg gggcccggag 300 gcggggcaga gcagtacgtgctgtacatgg tgagccgcaa cggctaccgc 350 acctgcaacg ccagccaggg cttcaagcgctgggagtgca accggccgca 400 cgccccgcac agccccatca agttctcgga gaagttccagcgctacagcg 450 ccttctctct gggctacgag ttccacgccg gccacgagta ctactacatc500 tccacgccca ctcacaacct gcactggaag tgtctgagga tgaaggtgtt 550cgtctgctgc gcctccacat cgcactccgg ggagaagccg gtccccactc 600 tcccccagttcaccatgggc cccaatgtga agatcaacgt gctggaagac 650 tttgagggag agaaccctcaggtgcccaag cttgagaaga gcatcagcgg 700 gaccagcccc aaacgggaac acctgcccctggccgtgggc atcgccttct 750 tcctcatgac gttcttggcc tcctagctct gccccctcccctgggggggg 800 agagatgggg cggggcttgg aaggagcagg gagcctttgg cctctccaag850 ggaagcctag tgggcctaga cccctcctcc catggctaga agtggggcct 900gcaccataca tctgtgtccg ccccctctac cccttccccc cacgtagggc 950 actgtagtggaccaagcacg gggacagcca tgggtcccgg gcggccttgt 1000 ggctctggta atgtttggtaccaaacttgg gggccaaaaa gggcagtgct 1050 caggactccc tggcccctgg tacctttccctgactcctgg tgccctctcc 1100 ctttgtcccc ccagagagac atatgccccc agagagagcaaatcgaagcg 1150 tgggaggcac ccccattgct ctcctccagg ggcagaacat ggggagggga1200 ctagatgggc aaggggcagc actgcctgct gcttccttcc cctgtttaca 1250gcaataaagc acgtcctcct cccccactcc cacttccagg attgtggttt 1300 ggattgaaaccaagtttaca agtagacacc cctggggggg cgggcagtgg 1350 acaaggatgg caaggggtgggcattggggt gccaggcagg catgtacaga 1400 ctctatatct ctatatataa tgtacagacagacagagtcc cttccctctt 1450 taaccccctg acctttcttg acttcccctt cagcttcagaccccttcccc 1500 accaggctta ggccccccca caccttgggg ggacccccct ggcccctctt1550 ttgtcttctg tgaagacagg acctatgcaa cgcacagaca cttttggaga 1600ccgtaaaaca acagcgcccc ctcccttcca gccctgagcc gggaaccatc 1650 tcccaggaccttgccctgct caccctatgt ggtcccacct atcctcctgg 1700 gcctttttca agtgctttggctgtgacttt catactctgc tcttagtcta 1750 aaaaaaataa actggagata a 1771 174126 DNA Homo sapien 17 cgctcgccat gggccactcc ccacctgtcc tgcctttgtgtgcctctgtg 50 tctttgctgg gtggcctgac ctttggttat gaactggcag tcatatcagg 100tgccctgctg ccactgcagc ttgactttgg gctaagctgc ttggagcagg 150 agttcctggtgggcagcctg ctcctggggg ctctcctcgc ctccctggtt 200 ggtggcttcc tcattgactgctatggcagg aagcaagcca tcctcgggag 250 caacttggtg ctgctggcag gcagcctgaccctgggcctg gctggttccc 300 tggcctggct ggtcctgggc cgcgctgtgg ttggcttcgccatttccctc 350 tcctccatgg cttgctgtat ctacgtgtca gagctggtgg ggccacggca400 gcggggagtg ctggtgtccc tctatgaggc aggcatcacc gtgggcatcc 450tgctctccta tgccctcaac tatgcactgg ctggtacccc ctggggatgg 500 aggcacatgttcggctgggc cactgcacct gctgtcctgc aatccctcag 550 cctcctcttc ctccctgctggtacagatga gactgcaaca cacaaggacc 600 tcatcccact ccagggaggt gaggcccccaagctgggccc ggggaggcca 650 cggtactcct ttctggacct cttcagggca cgcgataacatgcgaggccg 700 gaccacagtg ggcctggggc tggtgctctt ccagcaacta acagggcagc750 ccaacgtgct gtgctatgcc tccaccatct tcagctccgt tggtttccat 800gggggatcct cagccgtgct ggcctctgtg gggcttggcg cagtgaaggt 850 ggcagctaccctgaccgcca tggggctggt ggaccgtgca ggccgcaggg 900 ctctgttgct agctggctgtgccctcatgg ccctgtccgt cagtggcata 950 ggcctcgtca gctttgccgt gcccatggactcaggcccaa gctgtctggc 1000 tgtgcccaat gccaccgggc agacaggcct ccctggagactctggcctgc 1050 tgcaggactc ctctctacct cccattccaa ggaccaatga ggaccaaagg1100 gagccaatct tgtccactgc taagaaaacc aagccccatc ccagatctgg 1150agacccctca gcccctcctc ggctggccct gagctctgcc ctccctgggc 1200 cccctctgcccgctcggggg catgcactgc tgcgctggac cgcactgctg 1250 tgcctgatgg tctttgtcagtgccttctcc tttgggtttg ggccagtgac 1300 ctggcttgtc ctcagcgaga tctaccctgtggagatacga ggaagagcct 1350 tcgccttctg caacagcttc aactgggcgg ccaacctcttcatcagcctc 1400 tccttcctcg atctcattgg caccatcggc ttgtcctgga ccttcctgct1450 ctacggactg accgctgtcc tcggcctggg cttcatctat ttatttgttc 1500ctgaaacaaa aggccagtcg ttggcagaga tagaccagca gttccagaag 1550 agacggttcaccctgagctt tggccacagg cagaactcca ctggcatccc 1600 gtacagccgc atcgagatctctgcggcctc ctgaggaatc cgtctgcctg 1650 gaaattctgg aactgtggct ttggcagaccatctccagca tcctgcttcc 1700 taggccccag agcacaagtt ccagctggtc ttttgggagtggcccctgcc 1750 cccaaaggtg gtctgctttt gctggggtaa aaaggatgaa agtctgagaa1800 tgcccaactc ttcattttga gtctcaggcc ctgaaggttc ctgaggatct 1850agcttcatgc ctcagtttcc ccattgactt gcacatctct gcagtattta 1900 taagaagaatattctatgaa gtctttgttg caccatggac ttttctcaaa 1950 gaatctcaag ggtaccaatcctggcaggaa gtctctcccg atatcacccc 2000 taaatccaaa tgaggatatc atcttttctaatctcttttt tcaactggct 2050 gggacatttt cggaaggggg aagtctcttt ttttactcttatcatttttt 2100 ttttttgagg tggagtctca ttctgttgcc caggctggcc tgatcttggc2150 tcactgcaac ctccacctcc tgagttcaag cgattcttgt gcctcagcct 2200cctaagcagc tgggactaca ggcgcatgca accataccca gctaatttat 2250 ttttagcagagatggggttt cactgtgttg gccaggctgg tcgtgaactc 2300 ctgagctcaa gtgatccacccacctcagcc tcccagagtg ctaggattac 2350 aggccttttg actcttttat ctgagttttattgacccctc taattctctt 2400 acccagaata tttatccttc accagcaact ctgactctttgacgggaggc 2450 ctcagttcta gtccttggtc tgctggtgtc attgctgtag gaatgaccac2500 gggcctcagt ttccccattt gtataatggg aagcctgtac caggtcattc 2550ttaagatttc tcctgactcc agtgagctgg aattctaaat gctggtctag 2600 gagctgtctccaggatggtg caggatggct ttgcggaaag gagatgggtt 2650 tggaggccaa caaacctgcttgtcaatatt gcctttgcct cttggcagcc 2700 cttgaacttg agtaaataac aactccctgaacctcagttt cctcatctgc 2750 agaatgggga taattatgtc ccaggggtat atttagaccctgtttccttt 2800 caggagggtc cccagctggt ccagggcctg ggaaatttct acttatcctc2850 attacccagg tccctccttt ggaccctgta aagggtcagg gtgaatcaga 2900tgggggactg agcaagtagc tatgactgca gatcatgtaa ggaagggact 2950 gacaagaagctcccagatgc tggggagaat gaagagctaa aatagatcct 3000 aggtgctgga tgctttgtcatccatgcgtg cacatatggg tgctggcaga 3050 gcccccaagg actctggcct ctcgagttctcctatcttct ccattctaga 3100 tgcttccctt gtatccagtg atgtgctgga gctggctttgccaagcttgt 3150 gagagctggt tgctacattt tcaggatttt tacaagttgg taaacacagc3200 cattataaaa aattaaatga tttaaattta taattaagta aattacatta 3250aaacaaaaaa attatactca aaattcatta cttaatttta ctacctgtta 3300 ctattatctgtgcttttgag gctatttcta catagtaact cttatggaga 3350 cctaggggag acaccgcgcatctcttcctg attccccact caatgacatc 3400 atgttagtct ttggttgctt aactggctgtggggagtgtt tttgtatcac 3450 aaagattaga gaggactaca catcagggct tgatttattgtttgttgatt 3500 ttctagactt cagaacatgc tggataaaat gtcagtaatg caaattaaac3550 tttaaagtat gtcttgtttg tagccaatac atggtgtata gcaccaaaaa 3600atggagggat tattcttcca gtagttgaac actgtcatcc gtttcagctg 3650 acagctgctcaaatcattta agaaggagtt ctgacattca ttttcattgt 3700 tttacttttg tcttcctcactagtgtaaac aaaaatttca accagcattc 3750 atgccgaacc tatacccatt cttcagtgcctagctgtaca gttatcaggg 3800 atttttattt gtagtctaat tttgtcaaat catggccaaatcgcagtgat 3850 agttgacttt ggatacaagg tttggcaaaa aaaaaaatat taacaaaata3900 ttctgtaaga atcaattgtc tatatggaat ttaggataaa gaatatttac 3950aataaagaat atttacaata aagagtttat tattatttgt aagttgtgtg 4000 caacaaacataccctttatc tctgtaaaat ttatacacac aaaaattaac 4050 aaaagattct gtaagaattaattggctata tggaatttag gatagaatat 4100 ttacaataaa gagtatttac aataaa 412618 5615 DNA Homo Sapien unsure 429 unknown base 18 gcttcagtcc cgcgaccgaagcagggcgcg cagcagcgct gagtgccccg 50 gaacgtgcgt cgcgccccca gtgtccgtcgcgtccgccgc gccccgggcg 100 gggatggggc ggccagactg agcgccgcac ccgccatccagacccgccgg 150 ccctagccgc agtccctcca gccgtggccc cagcgcgcac gggcgatggc200 gaaggcgacg tccggtgccg cggggctgcg tctgctgttg ctgctgctgc 250tgccgctgct aggcaaagtg gcattgggcc tctacttctc gagggatgct 300 tactgggagaagctgtatgt ggaccaggcg gccggcacgc ccttgctgta 350 cgtccatgcc ctgcgggacgcccctgagga ggtgcccagc ttccgcctgg 400 gccagcatct ctacggcacg taccgcacncggctgcatga gaacaactgg 450 atctgcatcc aggaggacac cggcctcctc taccttaaccggagcctgga 500 ccatagctcc tgggagaagc tcagtgtccg caaccgcggc tttcccctgc550 tcaccgtcta cctcaaggtc ttcctgtcac ccacatccct tcgtgagggc 600gagtgccagt ggccaggctg tgcccgcgta tacttctcct tcttcaacac 650 ctcctttccagcctgcagct ccctcaagcc ccgggagctc tgcttcccag 700 agacaaggcc ctccttccgcattcgggaga accgaccccc aggcaccttc 750 caccagttcc gcctgctgcc tgtgcagttcttgtgcccca acatcagcgt 800 ggcctacagg ctcctggagg gtgagggtct gcccttccgctgcgccccgg 850 acagcctgga ggtgagcacg cgctgggccc tggaccgcga gcagcgggag900 aagtacgagc tggtggccgt gtgcaccgtg cacgccggcg cgcgcgagga 950ggtggtgatg gtgcccttcc cggtgaccgt gtacgacgag gacgactcgg 1000 cgcccaccttccccgcgggc gtcgacaccg ccagcgccgt ggtggagttc 1050 aagcggaagg aggacaccgtggtggccacg ctgcgtgtct tcgatgcaga 1100 cgtggtacct gcatcagggg agctggtgaggcggtacaca agcacgctgc 1150 tccccgggga cacctgggcc cagcagacct tccgggtggaacactggccc 1200 aacgagacct cggtccaggc caacggcagc ttcgtgcggg cgaccgtaca1250 tgactatagg ctggttctca accggaacct ctccatctcg gagaaccgca 1300ccatgcagct ggcggtgctg gtcaatgact cagacttcca gggcccagga 1350 gcgggcgtcctcttgctcca cttcaacgtg tcggtgctgc cggtcagcct 1400 gcacctgccc agtacctactccctctccgt gagcaggagg gctcgccgat 1450 ttgcccagat cgggaaagtc tgtgtggaaaactgccaggc gttcagtggc 1500 atcaacgtcc agtacaagct gcattcctct ggtgccaactgcagcacgct 1550 aggggtggtc acctcagccg aggacacctc ggggatcctg tttgtgaatg1600 acaccaaggc cctgcggcgg cccaagtgtg ccgaacttca ctacatggtg 1650gtggccaccg accagcagac ctctaggcag gcccaggccc agctgcttgt 1700 aacagtggaggggtcatatg tggccgagga ggcgggctgc cccctgtcct 1750 gtgcagtcag caagagacggctggagtgtg aggagtgtgg cggcctgggc 1800 tccccaacag gcaggtgtga gtggaggcaaggagatggca aagggatcac 1850 caggaacttc tccacctgct ctcccagcac caagacctgccccgacggcc 1900 actgcgatgt tgtggagacc caagacatca acatttgccc tcaggactgc1950 ctccggggca gcattgttgg gggacacgag cctggggagc cccgggggat 2000taaagctggc tatggcacct gcaactgctt ccctgaggag gagaagtgct 2050 tctgcgagcccgaagacatc caggatccac tgtgcgacga gctgtgccgc 2100 acggtgatcg cagccgctgtcctcttctcc ttcatcgtct cggtgctgct 2150 gtctgccttc tgcatccact gctaccacaagtttgcccac aagccaccca 2200 tctcctcagc tgagatgacc ttccggaggc ccgcccaggccttcccggtc 2250 agctactcct cttccggtgc ccgccggccc tcgctggact ccatggagaa2300 ccaggtctcc gtggatgcct tcaagatcct ggaggatcca aagtgggaat 2350tccctcggaa gaacttggtt cttggaaaaa ctctaggaga aggcgaattt 2400 ggaaaagtggtcaaggcaac ggccttccat ctgaaaggca gagcagggta 2450 caccacggtg gccgtgaagatgctgaaaga gaacgcctcc ccgagtgagc 2500 ttcgagacct gctgtcagag ttcaacgtcctgaagcaggt caaccaccca 2550 catgtcatca aattgtatgg ggcctgcagc caggatggcccgctcctcct 2600 catcgtggag tacgccaaat acggctccct gcggggcttc ctccgcgaga2650 gccgcaaagt ggggcctggc tacctgggca gtggaggcag ccgcaactcc 2700agctccctgg accacccgga tgagcgggcc ctcaccatgg gcgacctcat 2750 ctcatttgcctggcagatct cacaggggat gcagtatctg gccgagatga 2800 agctcgttca tcgggacttggcagccagaa acatcctggt agctgagggg 2850 cggaagatga agatttcgga tttcggcttgtcccgagatg tttatgaaga 2900 ggattcctac gtgaagagga gccagggtcg gattccagttaaatggatgg 2950 caattgaatc cctttttgat catatctaca ccacgcaaag tgatgtatgg3000 tcttttggtg tcctgctgtg ggagatcgtg accctagggg gaaaccccta 3050tcctgggatt cctcctgagc ggctcttcaa ccttctgaag accggccacc 3100 ggatggagaggccagacaac tgcagcgagg agatgtaccg cctgatgctg 3150 caatgctgga agcaggagccggacaaaagg ccggtgtttg cggacatcag 3200 caaagacctg gagaagatga tggttaagaggagagactac ttggaccttg 3250 cggcgtccac tccatctgac tccctgattt atgacgacggcctctcagag 3300 gaggagacac cgctggtgga ctgtaataat gcccccctcc ctcgagccct3350 cccttccaca tggattgaaa acaaactcta tggcatgtca gacccgaact 3400ggcctggaga gagtcctgta ccactcacga gagctgatgg cactaacact 3450 gggtttccaagatatccaaa tgatagtgta tatgctaact ggatgctttc 3500 accctcagcg gcaaaattaatggacacgtt tgatagttaa catttctttg 3550 tgaaaggtaa tggactcaca aggggaagaaacatgctgag aatggaaagt 3600 ctaccggccc tttctttgtg aacgtcacat tggccgagccgtgttcagtt 3650 cccaggtggc agactcgttt ttggtagttt gttttaactt ccaaggtggt3700 tttacttctg atagccggtg attttccctc ctagcagaca tgccacaccg 3750ggtaagagct ctgagtctta gtggttaagc attcctttct cttcagtgcc 3800 cagcagcacccagtgttggt ctgtgtccat cagtgaccac caacattctg 3850 tgttcacatg tgtgggtccaacacttacta cctggtgtat gaaattggac 3900 ctgaactgtt ggatttttct agttgccgccaaacaaggca aaaaaattta 3950 aacatgaagc acacacacaa aaaaggcagt aggaaaaatgctggccctga 4000 tgacctgtcc ttattcagaa tgagagactg cggggggggc ctgggggtag4050 tgtcaatgcc cctccagggc tggaggggaa gaggggcccc gaggatgggc 4100ctgggctcag cattcgagat cttgagaatg atttttttta aatcatgcaa 4150 cctttccttaggaagacatt tggttttcat catgattaag atgattccta 4200 gatttagcac aatggagagattccatgcca tctttactat gtggatggtg 4250 gtatcaggga agagggctca caagacacatttgtcccccg ggcccaccac 4300 atcatcctca cgtgttcggt actgagcagc cactacccctgatgagaaca 4350 gtatgaagaa agggggctgt tggagtccca gaattgctga cagcagaggc4400 tttgctgctg tgaatcccac ctgccaccag cctgcagcac accccacagc 4450caagtagagg cgaaacgagt ggctcatcct acctgttagg agcaggtagg 4500 gcttgtactcactttaattt gaatcttatc aacttactca taaagggaca 4550 ggctagctag ctgtgtcagaagtagcaatg acaatgacca aggactgcta 4600 cacctctgat tacaattctg atgtgaaaaagatggtgttt ggctcttata 4650 gagcctgtgt gaaaggccca tggatcagct cttcctgtgtttgtaattta 4700 atgctgctac aagatgtttc tgtttcttag attctgacca tgactcataa4750 gcttcttgtc attcttcatt gcttgtttgt ggtcacagat gcacaacact 4800cctccagtct tgtgggggca gcttttggga agtctcagca gctcttctgg 4850 ctgtgttgtcagcactgtaa cttcgcagaa aagagtcgga ttaccaaaac 4900 actgcctgct cttcagacttaaagcactga taggacttaa aatagtctca 4950 ttcaaatact gtattttata taggcatttcacaaaaacag caaaattgtg 5000 gcattttgtg aggccaaggc ttggatgcgt gtgtaatagagccttatggt 5050 gtgtgcgcac acacccagag gagagtttga aaaatgctta ttggacacgt5100 aacctggctc taatttgggc tgtttttcag atacactgtg ataagttctt 5150ttacaaatat ctatagacat ggtaaacttt tggttttcag atatgcttaa 5200 tgatagtcttactaaatgca gaaataagaa taaactttct caaattatta 5250 aaaatgccta cacagtaagtgtgaattgct gcaacaggtt tgttctcagg 5300 agggtaagaa ctccaggtct aaacagctgacccagtgatg gggaatttat 5350 ccttgaccaa tttatccttg accaataacc taattgtctattcctgagtt 5400 ataaaggtcc ccatccttat tagctctact ggaattttca tacacgtaaa5450 tgcagaagtt actaagtatt aagtattact gagtattaag tagtaatctg 5500tcagttatta aaatttgtaa aatctattta tgaaaggtca ttaaaccaga 5550 tcatgttcctttttttgtaa tcaaggtgac taagaaaatc agttgtgtaa 5600 ataaaatcat gtatc 561519 4315 DNA Homo Sapien 19 tgagagccaa gcaaagaaca ttaaggaagg aaggaggaatgaggctggat 50 acggtgcagt gaaaaaggca cttccaagag tggggcactc actacgcaca 100gactcgacgg tgccatcagc atgagaactt accgctactt cttgctgctc 150 ttttgggtgggccagcccta cccaactctc tcaactccac tatcaaagag 200 gactagtggt ttcccagcaaagaaaagggc cctggagctc tctggaaaca 250 gcaaaaatga gctgaaccgt tcaaaaaggagctggatgtg gaatcagttc 300 tttctcctgg aggaatacac aggatccgat tatcagtatgtgggcaagtt 350 acattcagac caggatagag gagatggatc acttaaatat atcctttcag400 gagatggagc aggagatctc ttcattatta atgaaaacac aggcgacata 450caggccacca agaggctgga cagggaagaa aaacccgttt acatccttcg 500 agctcaagctataaacagaa ggacagggag acccgtggag cccgagtctg 550 aattcatcat caagatccatgacatcaatg acaatgaacc aatattcacc 600 aaggaggttt acacagccac tgtccctgaaatgtctgatg tcggtacatt 650 tgttgtccaa gtcactgcga cggatgcaga tgatccaacatatgggaaca 700 gtgctaaagt tgtctacagt attctacagg gacagcccta tttttcagtt750 gaatcagaaa caggtattat caagacagct ttgctcaaca tggatcgaga 800aaacagggag cagtaccaag tggtgattca agccaaggat atgggcggcc 850 agatgggaggattatctggg accaccaccg tgaacatcac actgactgat 900 gtcaacgaca accctccccgattcccccag agtacatacc agtttaaaac 950 tcctgaatct tctccaccgg ggacaccaattggcagaatc aaagccagcg 1000 acgctgatgt gggagaaaat gctgaaattg agtacagcatcacagacggt 1050 gaggggctgg atatgtttga tgtcatcacc gaccaggaaa cccaggaagg1100 gattataact gtcaaaaagc tcttggactt tgaaaagaag aaagtgtata 1150cccttaaagt ggaagcctcc aatccttatg ttgagccacg atttctctac 1200 ttggggcctttcaaagattc agccacggtt agaattgtgg tggaggatgt 1250 agatgagcca cctgtcttcagcaaactggc ctacatctta caaataagag 1300 aagatgctca gataaacacc acaataggctccgtcacagc ccaagatcca 1350 gatgctgcca ggaatcctgt caagtactct gtagatcgacacacagatat 1400 ggacagaata ttcaacattg attctggaaa tggttcgatt tttacatcga1450 aacttcttga ccgagaaaca ctgctatggc acaacattac agtgatagca 1500acagagatca ataatccaaa gcaaagtagt cgagtacctc tatatattaa 1550 agttctagatgtcaatgaca acgccccaga atttgctgag ttctatgaaa 1600 cttttgtctg tgaaaaagcaaaggcagatc agttgattca gaccctgcat 1650 gctgttgaca aggatgaccc ttatagtggacaccaatttt cgttttcctt 1700 ggcccctgaa gcagccagtg gctcaaactt taccattcaagacaacaaag 1750 acaacacggc gggaatctta actcggaaaa atggctataa tagacacgag1800 atgagcacct atctcttgcc tgtggtcatt tcagacaacg actacccagt 1850tcaaagcagc actgggacag tgactgtccg ggtctgtgca tgtgaccacc 1900 acgggaacatgcaatcctgc catgcggagg cgctcatcca ccccacggga 1950 ctgagcacgg gggctctggttgccatcctt ctgtgcatcg tgatcctact 2000 agtgacagtg gtgctgtttg cagctctgaggcggcagcga aaaaaagagc 2050 ctttgatcat ttccaaagag gacatcagag ataacattgtcagttacaac 2100 gacgaaggtg gtggagagga ggacacccag gcttttgata tcggcaccct2150 gaggaatcct gaagccatag aggacaacaa attacgaagg gacattgtgc 2200ccgaagccct tttcctaccc cgacggactc caacagctcg cgacaacacc 2250 gatgtcagagatttcattaa ccaaaggtta aaggaaaatg acacggaccc 2300 cactgccccg ccatacgactccttggccac ttacgcctat gaaggcactg 2350 gctccgtggc ggattccctg agctcgctggagtcagtgac cacggatgca 2400 gatcaagact atgattacct tagtgactgg ggacctcgattcaaaaagct 2450 tgcagatatg tatggaggag tggacagtga caaagactcc taatctgttg2500 cctttttcat tttccaatac gacactgaaa tatgtgaagt ggctatttct 2550ttatatttat ccactactcc gtgaaggctt ctctgttcta cccgttccaa 2600 aagccaatggctgcagtccg tgtggatcca atgttagaga cttttttcta 2650 gtacactttt atgagcttccaaggggcaaa tttttatttt ttagtgcatc 2700 cagttaacca agtcagccca acaggcaggtgccggagggg aggacaggga 2750 acagtatttc cacttgttct cagggcagcg tgcccgcttccgctgtcctg 2800 gtgttttact acactccatg tcaggtcagc caactgccct aactgtacat2850 ttcacaggct aatgggataa aggactgtgc tttaaagata aaaatatcat 2900catagtaaaa gaaatgaggg catatcggct cacaaagaga taaactacat 2950 aggggtgtttatttgtgtca caaagaattt aaaataacac ttgcccatgc 3000 tatttgttct tcaagaactttctctgccat caactactat tcaaaacctc 3050 aaatccaccc atatgttaaa attctcattactcttaagga atagaagcaa 3100 attaaacggt aacatccaaa agcaaccaca aacctagtacgacttcattc 3150 cttccactaa ctcatagttt gttatatcct agactagaca tgcgaaagtt3200 tgcctttgta ccatataaag ggggagggaa atagctaata atgttaacca 3250aggaaatata ttttaccata catttaaagt tttggccacc acatgtatca 3300 cgggtcacttgaaattcttt cagctatcag taggctaatg tcaaaattgt 3350 ttaaaaattc ttgaaagaattttcctgaga caaattttaa cttcttgtct 3400 atagttgtca gtattattct actatactgtacatgaaagt agcagtgtga 3450 agtacaataa ttcatattct tcatatcctt cttacacgactaagttgaat 3500 tagtaaagtt agattaaata aaacttaaat ctcactctag gagttcagtg3550 gagaggttag agccagccac acttgaacct aataccctgc ccttgacatc 3600tggaaacctc tacatattta tataacgtga tacatttgga taaacaacat 3650 tgagattatgatgaaaacct acatattcca tgtttggaag acccttggaa 3700 gaggaaaatt ggattcccttaaacaaaagt gtttaagatt gtaattaaaa 3750 tgatagttga ttttcaaaag cattaattttttttcattgt ttttaacttt 3800 gctttcatga ccatcctgcc atccttgact ttgaactaatgataaagtaa 3850 tgatctcaaa ctatgacaga aaagtaatgt aaaatccatc caatctatta3900 tttctctaat tatgcaatta gcctcatagt tattatccag aggacccaac 3950tgaactgaac taatccttct ggcagattca aatcgtttat ttcacacgct 4000 gttctaatggcacttatcat tagaatctta ccttgtgcag tcatcagaaa 4050 ttccagcgta ctataatgaaaacatccttg ttttgaaaac ctaaaagaca 4100 ggctctgtat atatatatac ttaagaatatgctgacttca cttattagtc 4150 ttagggattt attttcaatt aatattaatt ttctacaaataattttagtg 4200 tcatttccat ttggggatat tgtcatatca gcacatattt tctgtttgga4250 aacacactgt tgtttagtta agttttaaat aggtgtatta cccaagaagt 4300aaagatggaa acgtt 4315 20 2521 DNA Homo Sapien 20 cggtggaggc cacagacacctcaaacctgg attccacaat tctacgttaa 50 gtgttggagt ttttattact ctgctgtaggaaagcctttg ccaatgctta 100 caaggaactg tttatccctg cttctctggg ttctgtttgatggaggtctc 150 ctaacaccac tacaaccaca gccacagcag actttagcca cagagccaag200 agaaaatgtt atccatctgc caggacaacg gtcacatttc caacgtgtta 250aacgtggctg ggtatggaat caattttttg tgctggaaga atacgtgggc 300 tccgagcctcagtatgtggg aaagctccat tccgacttag acaagggaga 350 gggcactgtg aaatacaccctctcaggaga tggcgctggc accgttttta 400 ccattgatga aaccacaggg gacattcatgcaataaggag cctagataga 450 gaagagaaac ctttctacac tcttcgtgct caggctgtggacatagaaac 500 cagaaagccc ctggagcctg aatcagaatt catcatcaaa gtgcaggata550 ttaatgataa tgagccaaag tttttggatg gaccttatgt tgctactgtt 600ccagaaatgt ctcctgtggg tgcatatgta ctccaggtca aggccacaga 650 tgcagatgacccgacctatg gaaacagtgc cagagtcgtt tacagcattc 700 ttcagggaca accttatttctctattgatc ccaagacagg tgttattaga 750 acagctttgc caaacatgga cagagaagtcaaagaacaat atcaagtact 800 catccaagcc aaggatatgg gaggacagct tggaggattagccggaacaa 850 caatagtcaa catcactctc accgatgtca atgacaatcc acctcgattc900 cccaaaagca tcttccactt gaaagttcct gagtcttccc ctattggttc 950agctattgga agaataagag ctgtggatcc tgattttgga caaaatgcag 1000 aaattgaatacaatattgtt ccaggagatg ggggaaattt gtttgacatc 1050 gtcacagatg aggatacacaagagggagtc atcaaattga aaaagccttt 1100 agattttgaa acaaagaagg catacactttcaaagttgag gcttccaacc 1150 ttcaccttga ccaccggttt cactcggcgg gccctttcaaagacacagct 1200 acggtgaaga tcagcgtgct ggacgtagat gagccaccgg ttttcagcaa1250 gccgctctac accatggagg tttatgaaga cactccggta gggaccatca 1300ttggcgctgt cactgctcaa gacctggatg taggcagcgg tgctgttagg 1350 tacttcatagattggaagag tgatggggac agctacttta caatagatgg 1400 aaatgaagga accatcgccactaatgaatt actagacaga gaaagcactg 1450 cgcagtataa tttctccata attgcgagtaaagttagtaa ccctttattg 1500 accagcaaag tcaatatact gattaatgtc ttagatgtaaatgaatttcc 1550 tccagaaata tctgtgccat atgagacagc cgtgtgtgaa aatgccaagc1600 caggacagat aattcagata gtcagtgctg cagaccgaga tctttcacct 1650gctgggcaac aattctcctt tagattatca cctgaggctg ctatcaaacc 1700 aaattttacagttcgtgact tcagaaacaa cacagcgggg attgaaaccc 1750 gaagaaatgg atacagccgcaggcagcaag agttgtattt cctccctgtt 1800 gtaatagaag acagcagcta ccctgtccagagcagcacaa acacaatgac 1850 tattcgagtc tgtagatgtg actctgatgg caccatcctgtcttgtaatg 1900 tggaagcaat ttttctacct gtaggactta gcactggggc gttgattgca1950 attctactat gcattgttat actcttagcc atagttgtac tgtatgtagc 2000actgcgaagg cagaagaaaa agcacaccct gatgacctct aaagaagaca 2050 tcagagacaacgtcatccat tacgatgatg aaggaggtgg ggaggaagat 2100 acccaggctt tcgacatcggggctctgaga aacccaaaag tgattgagga 2150 gaacaaaatt cgcagggata taaaaccagactctctctgt ttacctcgtc 2200 agagaccacc catggaagat aacacagaca taagggatttcattcatcaa 2250 aggctacagg aaaatgatgt agatccaact gccccaccaa tcgattcact2300 ggccacatat gcctacgaag ggagtgggtc cgtggcagag tccctcagct 2350ctatagactc tctcaccaca gaagccgacc aggactatga ctatctgaca 2400 gactggggaccccgctttaa agtcttggca gacatgtttg gcgaagaaga 2450 gagttataac cctgataaagtcacttaagg gagtcgtgga ggctaaaata 2500 caaccgagag gggagatttt t 2521 21736 DNA Homo Sapien 21 ggctctcacc ctcctctcct gcagctccag ctctgtgctctgcctctgag 50 gagaccatgg cccggcctct gtgtaccctg ctactcctga tggctaccct 100ggctggggct ctggcctcga gctccaagga ggagaatagg ataatcccag 150 gtggcatctatgatgcagac ctcaatgatg agtgggtaca gcgtgccctt 200 cacttcgcca tcagcgagtacaacaaggcc accgaagatg agtactacag 250 acgcccgctg caggtgctgc gagccagggagcagaccttt gggggggtga 300 attacttctt cgacgtagag gtgggccgca ccatatgtaccaagtcccag 350 cccaacttgg acacctgtgc cttccatgaa cagccagaac tgcagaagaa400 acagttatgc tctttcgaga tctacgaagt tccctgggag gacagaatgt 450ccctggtgaa ttccaggtgt caagaagcct aggggtctgt gccaggccag 500 tcacaccgaccaccacccac tcccaccccc tgtagtgctc ccacccctgg 550 actggtggcc cccaccctgcgggaggcctc cccatgtgcc tgtgccaaga 600 gacagacaga gaaggctgca ggagtcctttgttgctcagc agggcgctct 650 gccctccctc cttccttctt gcttctaata gacctggtacatggtacaca 700 cacccccacc tcctgcaatt aaacagtagc atcgcc 736 22 2025 DNAHomo Sapien 22 ggcagcggtg gcaggggctg caggagcaag tgaccaggag caggactggg 50gacaggcctg atcgcccctg cacgaaccag acccttcgcc gccctcacga 100 tgactacctctccgatcctg cagctgctgc tgcggctctc actgtgcggg 150 ctgctgctcc agagggcggagacaggctct aaggggcaga cggcggggga 200 gctgtaccag cgctgggaac ggtaccgcagggagtgccag gagaccttgg 250 cagccgcgga accgccttca ggcctcgcct gtaacgggtccttcgatatg 300 tacgtctgct gggactatgc tgcacccaat gccactgccc gtgcgtcctg350 cccctggtac ctgccctggc accaccatgt ggctgcaggt ttcgtcctcc 400gccagtgtgg cagtgatggc caatggggac tttggagaga ccatacacaa 450 tgtgagaacccagagaagaa tgaggccttt ctggaccaaa ggctcatctt 500 ggagcggttg caggtcatgtacactgtcgg ctactccctg tctctcgcca 550 cactgctgct agccctgctc atcttgagtttgttcaggcg gctacattgc 600 actagaaact atatccacat caacctgttc acgtctttcatgctgcgagc 650 tgcggccatt ctcagccgag accgtctgct acctcgacct ggcccctacc700 ttggggacca ggcccttgcg ctgtggaacc aggccctcgc tgcctgccgc 750acggcccaga tcgtgaccca gtactgcgtg ggtgccaact acacgtggct 800 gctggtggagggcgtctacc tgcacagtct cctggtgctc gtgggaggct 850 ccgaggaggg ccacttccgctactacctgc tcctcggctg gggggccccc 900 gcgcttttcg tcattccctg ggtgatcgtcaggtacctgt acgagaacac 950 gcagtgctgg gagcgcaacg aagtcaaggc catttggtggattatacgga 1000 cccccatcct catgaccatc ttgattaatt tcctcatttt tatccgcatt1050 cttggcattc tcctgtccaa gctgaggaca cggcaaatgc gctgccggga 1100ttaccggctg aggctggctc gctccacgct gacgctggtg cccctgctgg 1150 gtgtccacgaggtggtgttt gctcccgtga cagaggaaca ggcccggggc 1200 gccctgcgct tcgccaagctcggctttgag atcttcctca gctccttcca 1250 gggcttcctg gtcagcgtcc tctactgcttcatcaacaag gaggtgcagt 1300 cggagatccg ccgtggctgg caccactgcc gcctgcgccgcagcctgggc 1350 gaggagcaac gccagctccc ggagcgcgcc ttccgggccc tgccctccgg1400 ctccggcccg ggcgaggtcc ccaccagccg cggcttgtcc tcggggaccc 1450tcccagggcc tgggaatgag gccagccggg agttggaaag ttactgctag 1500 ggggcgggatccccgtgtct gttcagttag catggattta ttgagtgcca 1550 actgcgtgcc aggcccagtacggaggacgc tggggaaatg gtgaaggaaa 1600 cagaaaaaag gtccctgccc ttctggagatgacaactgag tggggaaaac 1650 agaccgtgaa cacaaaacat caagttccac acacgctatggaatggttat 1700 gaagggaagc gagaaggggg cctagggtgg tctgggaggc gtctccaagg1750 aggtgacact taagccatcc ccgaaagagg tgaaagagat cactttgggg 1800agagctggag aacaggattc taggcggaag cgatagcata ggcaaaggcc 1850 cttgggcaggaaggcgctca gccttggctg gagtagaatt aagtcagagc 1900 caacaggttg gggagagacagagaagtggg caggggcacc caagttggga 1950 tttcatttca ggtgcattgg agattcttaggagtgtctct tgggggtaat 2000 attttatttt ttaaaaaatg aggat 2025 23 3168 DNAHomo Sapien 23 gccagagcgt gagccgcgac ctccgcgcag gtggtcgcgc cggtctccgc 50ggaaatgttg tccaaagttc ttccagtcct cctaggcatc ttattgatcc 100 tccagtcgagggtcgaggga cctcagactg aatcaaagaa tgaagcctct 150 tcccgtgatg ttgtctatggcccccagccc cagcctctgg aaaatcagct 200 cctctctgag gaaacaaagt caactgagactgagactggg agcagagttg 250 gcaaactgcc agaagcctct cgcatcctga acactatcctgagtaattat 300 gaccacaaac tgcgccctgg cattggagag aagcccactg tggtcactgt350 tgagatcgcc gtcaacagcc ttggtcctct ctctatccta gacatggaat 400acaccattga catcatcttc tcccagacct ggtacgacga acgcctctgt 450 tacaacgacacctttgagtc tcttgttctg aatggcaatg tggtgagcca 500 gctatggatc ccggacaccttttttaggaa ttctaagagg acccacgagc 550 atgagatcac catgcccaac cagatggtccgcatctacaa ggatggcaag 600 gtgttgtaca caattaggat gaccattgat gccggatgctcactccacat 650 gctcagattt ccaatggatt ctcactcttg ccctctatct ttctctagct700 tttcctatcc tgagaatgag atgatctaca agtgggaaaa tttcaagctt 750gaaatcaatg agaagaactc ctggaagctc ttccagtttg attttacagg 800 agtgagcaacaaaactgaaa taatcacaac cccagttggt gacttcatgg 850 tcatgacgat tttcttcaatgtgagcaggc ggtttggcta tgttgccttt 900 caaaactatg tcccttcttc cgtgaccacgatgctctcct gggtttcctt 950 ttggatcaag acagagtctg ctccagcccg gacctctctagggatcacct 1000 ctgttctgac catgaccacg ttgggcacct tttctcgtaa gaatttcccg1050 cgtgtctcct atatcacagc cttggatttc tatatcgcca tctgcttcgt 1100cttctgcttc tgcgctctgt tggagtttgc tgtgctcaac ttcctgatct 1150 acaaccagacaaaagcccat gcttctccta aactccgcca tcctcgtatc 1200 aatagccgtg cccatgcccgtacccgtgca cgttcccgag cctgtgcccg 1250 ccaacatcag gaagcttttg tgtgccagattgtcaccact gagggaagtg 1300 atggagagga gcgcccgtct tgctcagccc agcagccccctagcccaggt 1350 agccctgagg gtccccgcag cctctgctcc aagctggcct gctgtgagtg1400 gtgcaagcgt tttaagaagt acttctgcat ggtccccgat tgtgagggca 1450gtacctggca gcagggccgc ctctgcatcc atgtctaccg cctggataac 1500 tactcgagagttgttttccc agtgactttc ttcttcttca atgtgctcta 1550 ctggcttgtt tgccttaacttgtaggtacc agctggtacc ctgtggggca 1600 acctctccag ttccccagga ggtccaagccccttgccaag ggagttgggg 1650 gaaagcagca gcagcagcag gagcgactag agtttttcctgccccattcc 1700 ccaaacagaa gcttgcagag ggtttgtctt tgctgcccct ctcccctacc1750 tggcccattc actgagtctt ctcagcagac catttcaaat tattaataaa 1800tgggccacct ccctcttctt caaggagcat ccgtgatgct cagtgttcaa 1850 aaccacagccacttagtgat cagctcccta aaaccatgcc taagtacagg 1900 cggattagct atcttccaacaatgctgacc accagacaat tactgcattt 1950 ttccagaagc ccactattgc ctttgtagtgctttcggccc agttctggcc 2000 tcagcctcaa agtgcaccga ctagttgctt gcctatacctggcacctcat 2050 taagatgctg ggcagcagta taacaggagg aagagatccc tctcctttgg2100 tcagattatt atgttctcag ttctctctcc ctgctacccc tttctctgca 2150gatagataga cactggcatt atccctttag gaagaggggg gggcagcaag 2200 agagcctatttgggacagca ttcctctctc tctgctgctg tgacatctcc 2250 ctctccttgc tggctccatctttcgtctgc actaccaatt caatgccctt 2300 catccaatgg gtatctattt ttgtgtgtgattatagtaac tactccctgc 2350 tttatatgcc accctcttcc ttctctttga cccctgtgactctttctgta 2400 actttcccag tgacttcccc tagccctgac ccaggcacta ggccttggtg2450 acttcctggg gccaagaaac taaggaaact cggctttgca acaggcatta 2500ctcgccattg attggtgccc acccagggca cactgtcgga gttctatcac 2550 ttgcttgacccctggaccca taaaccagtc cactgttata cccggggcac 2600 tctaaccatc acaatcaatcaatcaaattc ccttaaattt gtatggcact 2650 ggaactttgg caaagcactt ttgacaagttgtgtctgatt ggagcttcat 2700 gatagccttg tgacatcttt agggcaggat tcttatccccattttgcaga 2750 tgaaaaccct gagtcacaga tttctgtggg actgtggatc tcactggaag2800 ctatccaaga gcccactgtc accttctaga ccacatgata gggctagaca 2850gctcagttca ccatgattct cttctgtcac ctctgctggc acaccagtgg 2900 caaggcccagaatggcgacc tctctttagc tcaatttctg ggcctgaggt 2950 gctcagactg cccccaagatcaaatctctc ctggctgtag taacccagtg 3000 gaatgaattt ggacatgccc caatgcttctatatgctaag tgaaatctgt 3050 gtctgtaatt tgttgggggg tggatagggt ggggtctccatctacttttt 3100 gtcaccatca tctgaaatgg ggaaatatgt aaataaatat atcagcaaag3150 caaaaagaaa aaaaaaaa 3168 24 2837 DNA Homo Sapien 24 tatcacaggattgtctactt cagcaatagc aactaatgga tttgtaagag 50 gaggaggagc atattatttaatatctagaa gtctagggcc agaatttggt 100 ggtgcaattg gtctaatctt cgcctttgccaacgctgttg cagttgctat 150 gtatgtggtt ggatttgcag aaaccgtggt ggagttgcttaaggaacatt 200 ccatacttat gatagatgaa atcaatgata tccgaattat tggagccatt250 acagtcgtga ttcttttagg tatctcagta gctggaatgg agtgggaagc 300aaaagctcag attgttcttt tggtgatcct acttcttgct attggtgatt 350 tcgtcataggaacatttatc ccactggaga gcaagaagcc aaaagggttt 400 tttggttata aatctgaaatatttaatgag aactttgggc ccgattttcg 450 agaggaagag actttctttt ctgtatttgccatctttttt cctgctgcaa 500 ctggtattct ggctggagca aatatctcag gtgatcttgcagatcctcag 550 tcagccatac ccaaaggaac actcctagcc attttaatta ctacattggt600 ttacgtagga attgcagtat ctgtaggttc ttgtgttgtt cgagatgcca 650ctggaaacgt taatgacact atcgtaacag agctaacaaa ctgtacttct 700 gcagcctgcaaattaaactt tgatttttca tcttgtgaaa gcagtccttg 750 ttcctatggc ctaatgaacaacttccaggt aatgagtatg gtgtcaggat 800 ttacaccact aatttctgca ggtatattttcagccactct ttcttcagca 850 ttagcatccc tagtgagtgc tcccaaaata tttcaggctctatgtaagga 900 caacatctac ccagctttcc agatgtttgc taaaggttat gggaaaaata950 atgaacctct tcgtggctac atcttaacat tcttaattgc acttggattc 1000atcttaattg ctgaactgaa tgttattgca ccaattatct caaacttctt 1050 ccttgcatcatatgcattga tcaatttttc agtattccat gcatcacttg 1100 caaaatctcc aggatggcgtcctgcattca aatactacaa catgtggata 1150 tcacttcttg gagcaattct ttgttgcatagtaatgttcg tcattaactg 1200 gtgggctgca ttgctaacat atgtgatagt ccttgggctgtatatttatg 1250 ttacctacaa aaaaccagat gtgaattggg gatcctctac acaagccctg1300 acttacctga atgcactgca gcattcaatt cgtctttctg gagtggaaga 1350ccacgtgaaa aactttaggc cacagtgtct tgttatgaca ggtgctccaa 1400 actcacgtccagctttactt catcttgttc atgatttcac aaaaaatgtt 1450 ggtttgatga tctgtggccatgtacatatg ggtcctcgaa gacaagccat 1500 gaaagagatg tccatcgatc aagccaaatatcagcgatgg cttattaaga 1550 acaaaatgaa ggcattttat gctccagtac atgcagatgacttgagagaa 1600 ggtgcacagt atttgatgca ggctgctggt cttggtcgta tgaagccaaa1650 cacacttgtc cttggattta agaaagattg gttgcaagca gatatgaggg 1700atgtggatat gtatataaac ttatttcatg atgcttttga catacaatat 1750 ggagtagtggttattcgcct aaaagaaggt ctggatatat ctcatcttca 1800 aggacaagaa gaattattgtcatcacaaga gaaatctcct ggcaccaagg 1850 atgtggtagt aagtgtggaa tatagtaaaaagtccgattt agatacttcc 1900 aaaccactca gtgaaaaacc aattacacac aaagttgaggaagaggatgg 1950 caagactgca actcaaccac tgttgaaaaa agaatccaaa ggccctattg2000 tgcctttaaa tgtagctgac caaaagcttc ttgaagctag tacacagttt 2050cagaaaaaac aaggaaagaa tactattgat gtctggtggc tttttgatga 2100 tggaggtttgaccttattga taccttacct tctgacgacc aagaaaaaat 2150 ggaaagactg taagatcagagtattcattg gtggaaagat aaacagaata 2200 gaccatgacc ggagagcgat ggctactttgcttagcaagt tccggataga 2250 cttttctgat atcatggttc taggagatat caataccaaaccaaagaaag 2300 aaaatattat agcttttgag gaaatcattg agccatacag acttcatgaa2350 gatgataaag agcaagatat tgcagataaa atgaaagaag atgaaccatg 2400gcgaataaca gataatgagc ttgaacttta taagaccaag acataccggc 2450 agatcaggttaaatgagtta ttaaaggaac attcaagcac agctaatatt 2500 attgtcatga gtctcccagttgcacgaaaa ggtgctgtgt ctagtgctct 2550 ctacatggca tggttagaag ctctatctaaggacctacca ccaatcctcc 2600 tagttcgtgg gaatcatcag agtgtcctta ccttctattcataaatgttc 2650 tatacagtgg acagccctcc agaatggtac ttcagtgcct agtgtagtaa2700 cctgaaatct tcaatgacac attaacatca caatggcgaa tggtgacttt 2750tctttcacga tttcattaat ttgaaagcac acaggaaagc ttgctccatt 2800 gataacgtgtatggagactt cggttttagt caattcc 2837 25 4709 DNA Homo Sapien 25 gagcttgtccagacgaagcc tcgcagggat gggttggagc ctgggccgtg 50 cttcgctcag gcagcgtttgaggcagaccc agcagggtcc tcctggggcc 100 ttcctgcctt tgaactgcgg tggcgggcgggcgcacggtc tcctgtacgc 150 cctagactag gggccgccat ctccatggcc acggccgtgagccggccctg 200 cgccggcagg tcgcgggaca tactgtggcg cgttttgggc tggaggatag250 ttgcaagtat tgtttggtca gtgctatttc tacccatctg caccacagta 300tttataattt tcagcaggat tgatttgttt catcctatac agtggctgtc 350 tgattctttcagtgacctgt atagttccta tgtaatcttt tacttcctgc 400 tgctgtcagt ggtaataataataataagta ttttcaatgt ggagttctat 450 gcagttgtgc cttctattcc ttgctccagactagctctga tagggaagat 500 cattcatcct cagcaactca tgcactcatt tattcatgctgcaatgggaa 550 tggtgatggc ctggtgtgct gcagtgataa cccagggcca gtacagcttt600 cttgtggttc cctgcactgg tactaacagc tttggtagcc ctgctgcgca 650aacctgctta aatgaatatc atcttttttt cctactgact ggagcattta 700 tgggctatagctatagcctc ctgtattttg ttaacaacat gaactatctt 750 ccatttccca tcatacagcaatacaagttc ttgcgtttta ggagatctct 800 gctcttatta gttaaacaca gttgtgtggaatcactgttc ctggttagaa 850 atttctgcat tttatattat tttcttggct atattcccaaagcttggatt 900 agcactgcta tgaaccttca catagatgag caggttcata ggccacttga950 cacagtgagt ggcctcttaa atctctcgtt actctaccat gtctggctgt 1000gtggtgtctt tctcctgacg acttggtatg tctcatggat actcttcaaa 1050 atctatgccacagaggctca tgtgtttcct gttcaaccac catttgcaga 1100 agggtcagat gagtgccttccaaaagtgtt aaatagcaat cctcccccca 1150 tcataaagta tttagccttg caggacctgatgttgctttc tcaatattct 1200 ccttcacgaa gacaagaagt tttcagcctc agccaaccaggtggacatcc 1250 ccacaattgg acagccattt caagggagtg tttgaatctt ttaaatggta1300 tgactcagaa actgattctc tatcaagaag ctgctgctac gaatgggaga 1350gtgtcttcat cttacccagt ggaacctaag aaattaaatt ctccagaaga 1400 aactgcttttcagacaccaa aatctagcca gatgcctcgg ccttcagtgc 1450 caccattagt taaaacatcactgttttctt caaaattatc tacacctgat 1500 gttgtgagcc catttgggac cccatttggctctagtgtaa tgaatcggat 1550 ggctggaatt tttgatgtaa acacctgcta tgggtcaccgcaaagtcctc 1600 agctaataag aagggggcca agattgtgga catcagcttc tgatcagcaa1650 atgactgaat tttctaatcc ttctccatct acctctatta gtgctgaggg 1700taagacaatg agacaaccca gtgtgattta ttcatggatt cagaataaac 1750 gtgaacagattaagaatttc ttgtcaaaac gggtgctgat aatgtatttt 1800 ttcagtaagc acccagaggcctccattcag gctgtttttt cagatgccca 1850 aatgcatatt tgggcattag aaggtctgtcgcacttagta gcagcatcat 1900 ttacagagga tagatttgga gttgtccaga cgacactaccagctatcctt 1950 aatactttgt tgacactgca agaggcagtc gacaagtact ttaagcttcc2000 tcatgcttcc agtaaaccac cccggatttc aggaagcctt gtggacactt 2050catataaaac attaagattt gcattcagag catcactgaa aactgccatc 2100 tatcgaataactactacatt tggtgaacat ctgaatgctg tgcaagcatc 2150 tgcagaacat cagaaaagacttcaacagtt cttggagttc aaagaatagt 2200 taagtaatat aaactgtgtt cattacactgctgatacaac tacagatggg 2250 acagtaaatg ttcagcattc ttggatcaga agaaaacggactaattagat 2300 gcttcctttg tcgtggtggt tgctttgaaa actatacttt aatgggagaa2350 atcatggaaa gaaattctca acagaataac tgaaaactgc cttttctgta 2400ccgattgctt tttgtgtgtg tggtataata aaatctttat tcaattttac 2450 agaagcattgatggcagtcg aaatgtctct agctcatata acttaatagt 2500 aataactaaa aaacttttagaatttacttt tgaaaggagg gaagccagtt 2550 ctgaaatgag tataggttga tttcatagtcttcttaatta agagtttagc 2600 tctttgtaaa ctcaaaatac ataaactttt taagtgtagtttcatttact 2650 gaaggataaa aatggtaaca gtgcagcaat attcacaaaa aatattgtct2700 aacggacata ttttgttaat ctgttaggtt gggtttttgt ttccagggac 2750aaattaaatt tgtatgatta cccaaaaaag ggtctcagtt tacagatgct 2800 aactctatataaaggaatgt ggaaaaactc agttcttaag ttacaagatt 2850 aaaaattcac atttggtctttaagaaacaa ttgactgaca tctatgaatt 2900 tattttgtat catgctagta aacacgaagtattaatgtat gggtattttc 2950 ccagctagtt ttgctttctt tttctggagc aaaacattaagtgattgcag 3000 agtttttcaa gcaagagaaa aaggtttgca aaaaaaccca ggaaatgttc3050 ccttttttcc ccaccattca tcttcattag atcaaattct gtgaaacttg 3100tctggtctct caaagggagc agcctctgta gtgttaaatg gctaattaaa 3150 ataggaagatctttatagcc agaaacaact tagtcatcaa atagcaagtg 3200 aaaccaaaac gtcagagggattactgtact tggaagtatg ttgtgtgtcc 3250 caaatgtgaa cgaagtattg ttagaatttattagatcagc ttctttggag 3300 atcaaagatt ggaaatccta gtcatagata ttcactggactggctttgga 3350 ctgaaatgct cctttgtaat tcttttccta ttgtcttttc cttctagtgt3400 cccaaaatat tttctttaaa gtcagcacag tactgtatat gaatctttaa 3450tgtggtatca tatatgtcta cttttgtctg attcatcgat gtattatatc 3500 tttataattgaatattttag ctccgggtcc tgttgcccct tcaagcagta 3550 catgccaaat tataaataggtgctactggc cttgagcata tcactgtggg 3600 acagttcccc aattgtcaag tgtttagatatgtagactat tgccatttgt 3650 ttttttgttt tggttttgct ttgtgtctga agctgaattgatttcttttt 3700 tttgaatgtg aaagttgaat ttcaaacgta gtcatttctt acagatggcc3750 aagacagaaa attgtggcta ggttgactga gaactgttgt cttccatgta 3800ttaacacaat taagcttttt atattccact ctctgtgctg accctggctg 3850 aggcattttgggagacaagg actctgaatc ttctgcttcc attaaagaag 3900 aactgtgata ttcaacattggatttctgag aataaagata ggatgattcc 3950 tttgaacttt gacttacttg tataaaatgtccagctaggt taggtttttg 4000 ccatttccta tatactttgg gtaaagctac atttgatgagcaatgtgaat 4050 gtttctgaga atgttcattc ctgttttctc ttaagagaat gtgctgtgta4100 ctaaatacag gccacatagt gtctgcctgt tgaagatctg gaaactgcct 4150ccccagatct gtattgtatt tggtaggtaa gggggtcagt ttctttttct 4200 cattgtgtgttgataatcta cacaccatct gttggaacca gggtgttatt 4250 atggggaact cctcctgtgtactaggagga ggaccttagg gagaccaaga 4300 ggagagaagc atttcctttg atgaagtcacatcctgtcta tgagcccact 4350 aatgctgtaa cattggcctg aaagagagtg ttctttaaaagcctttctcg 4400 gctgttagta taaaaacatg atggtatcag ctcttagcat gtttgcttga4450 cccttatgga aggtataaat ccacagaact tccttcccag agaactggga 4500aattgtccta gaaataaacc ttgtacagtt gagtggacat ggataagcaa 4550 caatttgttactttgcagga tttgttcctt ggtaattgtt tggtgtgtca 4600 tcctgtaaat attcatgatagtctgtttat atccttttgt atatcgttga 4650 tactggattg ggtagaaaaa taaattggcaatttaaaaaa atggaacagt 4700 taattgaaa 4709 26 6310 DNA Homo Sapien 26gatgggggcc ccgtttgtct gggccttggg ccttttgatg ctgcagatgc 50 tgctctttgtggctggggaa cagggcacac aggatatcac cgatgccagc 100 gaaagggggc tccacatgcagaagctgggg tctgggtcag tgcaggctgc 150 gctggcggag ctggtggccc tgccctgtctctttaccctg cagccacggc 200 caagcgcagc ccgagatgcc cctcggataa agtggaccaaggtgcggact 250 gcgtcgggcc agcgacagga cttgcccatc ctggtggcca aggacaatgt300 cgtgagggtg gccaaaagct ggcagggacg agtgtcactg ccttcctacc 350cccggcgccg agccaacgcc acgctacttc tggggccact gagggccagt 400 gactctgggctgtaccgctg ccaggtggtg aggggcatcg aggatgagca 450 ggacctggtg cccttggaggtgacaggtgt tgtgttccac taccgatcag 500 cccgggaccg ctatgcactg accttcgctgaggcccagga ggcctgccgt 550 ctcagctcag ccatcattgc agcccctcgg catctacaggctgcctttga 600 ggatggcttt gacaactgtg atgctggctg gctctctgac cgcactgttc650 ggtatcctat cacccagtcc cgtcctggtt gctatggcga ccgtagcagc 700cttccagggg ttcggagcta tgggaggcgc aacccacagg aactctacga 750 tgtgtattgctttgcccggg agctgggggg cgaggtcttc tacgtgggcc 800 cggcccgccg cctgacactggccggcgcgc gtgcacagtg ccgccgccag 850 ggtgccgcgc tggcctcggt gggacagctgcacctggcct ggcatgaggg 900 cctggaccag tgcgacccgg gctggctggc cgacggcagcgtgcgctacc 950 cgatccagac gccgcgccgg cgctgcgggg gcccagcccc gggcgtgcgc1000 accgtctacc gcttcgctaa ccggaccggc ttcccctcac ccgccgagcg 1050cttcgacgcc tactgcttcc gagctcatca ccccacgtca caacatggag 1100 acctagagaccccatcctct ggggatgagg gggagattct gtcagcagag 1150 gggcccccag ttagagaactggagcccacc ctggaggagg aagaggtggt 1200 cacccctgac ttccaggagc ctctggtgtccagtggggaa gaagaaaccc 1250 tgattttgga ggagaagcag gagtctcaac agaccctcagccctacccct 1300 ggggacccca tgctggcctc atggcccact ggggaagtgt ggctaagcac1350 ggtggccccc agccctagcg acatgggggc aggcactgca gcaagttcac 1400acacggaggt ggccccaact gaccctatgc ctaggagaag ggggcgcttc 1450 aaagggttgaatgggcgcta cttccagcag caggaaccgg agccggggct 1500 gcaagggggg atggaggccagcgcccagcc ccccacctca gaggctgcag 1550 tgaaccaaat ggagcctccg ttggccatggcagtcacaga gatgttgggc 1600 agtggccaga gccggagccc ctgggctgat ctgaccaatgaggtggatat 1650 gcctggagct ggttctgctg gtggcaagag ctccccagag ccctggctgt1700 ggccccctac catggtccca cccagcatct caggccacag cagggcccct 1750gtcctggagc tagagaaagc cgagggcccc agtgccaggc cagccacccc 1800 agacctgttttggtccccct tggaggccac tgtctcagct cccagccctg 1850 ccccctggga ggcattccctgtggccacct ccccagatct ccctatgatg 1900 gccatgctgc gtggtcccaa agagtggatgctaccacacc ccacccccat 1950 ctccaccgag gccaatagag ttgaggcaca tggtgaggccaccgccacgg 2000 ctccaccctc ccctgctgca gagaccaagg tgtattccct gcctctctct2050 ttgaccccaa caggacaggg tggagaggcc atgcccacaa cacctgagtc 2100ccccagggca gacttcagag aaactgggga gaccagccct gctcaggtca 2150 acaaagctgagcactccagc tccagcccat ggccttctgt aaacaggaat 2200 gtggctgtag gttttgtccccactgagact gccactgagc caacgggcct 2250 caggggtatc ccggggtctg agtctggggtcttcgacaca gcagaaagcc 2300 ccacttctgg cttgcaggcc actgtagatg aggtgcaggacccctggccc 2350 tcagtgtaca gcaaagggct ggatgcaagt tccccatctg cccccctggg2400 gagccctgga gtcttcttgg tacccaaagt caccccaaat ttggagcctt 2450gggttgctac agatgaagga cccactgtga atcccatgga ttccacagtc 2500 acgccggcccccagtgatgc tagtggaatt tgggaacctg gatcccaggt 2550 gtttgaagaa gccgaaagcaccaccttgag ccctcaggtg gccctggata 2600 caagcattgt gacgcccctc acgaccctggagcaggggga caaggttgga 2650 gttccagcca tgtctacact gggctcctca agctcccaaccccacccaga 2700 gccagaggat caggtggaga cccagggaac atcaggagct tcagtgcctc2750 cgcatcagag cagtccccta gggaaaccgg ctgttcctcc tgggacaccg 2800actgcagcca gtgtgggcga gtctgcctca gtttcctcag gggagcctac 2850 ggtaccgtgggacccctcca gcaccctgct gcctgtcacc ctgggcatag 2900 aggacttcga actggaggtcctggcaggga gcccgggtgt agagagcttc 2950 tgggaggagg tggcaagtgg agaggagccagccctgccag ggacccctat 3000 gaatgcaggt gcggaggagg tgcactcaga tccctgtgagaacaaccctt 3050 gtcttcatgg agggacatgt aatgccaatg gcaccatgta tggctgtagc3100 tgtgatcagg gcttcgccgg ggagaactgt gagattgaca ttgatgactg 3150cctctgcagc ccctgtgaga atggaggcac ctgtattgat gaggtcaatg 3200 gctttgtctgcctttgcctc cccagctatg ggggcagctt ttgtgagaaa 3250 gacaccgagg gctgtgaccgcggctggcat aagttccagg gccactgtta 3300 ccgctatttt gcccaccgga gggcatgggaagatgccgag aaggactgcc 3350 gccgccgctc cggccacctg accagcgtcc actcaccggaggaacacagc 3400 ttcattaata gctttgggca tgaaaacacg tggatcggcc tgaacgacag3450 gatcgtggag agagatttcc agtggacgga caacaccggg ctgcaatttg 3500agaactggcg agagaaccag ccggacaatt tcttcgcggg tggcgaggac 3550 tgtgtggtgatggtggcgca tgaaagcggg cgctggaacg atgtcccctg 3600 caactacaac ctaccctatgtctgcaagaa gggcacagtg ctctgtggtc 3650 cccctccggc agtggagaat gcctcactcatcggtgcccg caaggccaag 3700 aacaatgtcc atgccactgt aaggtaccag tgcaatgaaggatttgccca 3750 gcaccatgtg gtcaccattc gatgccggag caatggcaag tgggacaggc3800 cccaaattgt ctgcaccaaa cccagacgtt cacatcggat gcggggacac 3850caccaccacc accaacacca ccaccagcat caccaccaca aatcccgcaa 3900 ggagcgcagaaaacacaaga aacacccaac ggaggactgg gagaaggacg 3950 aagggaattt ttgctgaagaaccagaaaaa agaaagcaca acacctttcc 4000 catgcctcct ctggagcctt cgcctggggagacagaaccc agagagaaac 4050 aagagagtcc agaagtccct gaaccccaaa ctgttctcgcaaaaaaaata 4100 ttcctttgaa caaaggtctt cttttccttt ttttacatac acaagatctt4150 cttggcaggt ggagccaggt gtctgaaaag ttcattctcg tctggctgaa 4200ctctgggagt gtgtcccagc tgagggaagc acaagtagca aagctcattg 4250 gtctggtctcttgtttgcca ggctgattga agcaggcctt gatgagggtg 4300 catgagtgta tgtttgcattcacatgaagg aattgctttt cacaccagaa 4350 attcagactt agtcaatgtt ggctgaattcctaaatccag gaagaagcct 4400 ggacgtaggg tcattagctt tgggaataga aggctacacagaagcacact 4450 gtttttgaac ttgacaacag ctctcccttt accctggact tcagcccaag4500 ttccgtcttt ggtcttggtg gataaacaca cagtgtggag atcccacgta 4550ctgcatttta gggatgtttt taggacaacc tccctccatg ccttcagagt 4600 taggagtgagaatgatcaaa gcaatatgta ggtgatggag ggagagtgta 4650 ttgctaaccc ttccaggtctagtccagcgc tgagatttgg tggttctgca 4700 tgtgtgatga atctctttca cacaaatagacgagaggata tttagggcta 4750 gatgagccca gatttcttcc ccctccatct ctcagggagacaaagaacct 4800 ccttcctgga ccaaggaggt gctgccaagt tttctagccc agtgcacata4850 cccagtcctt aagcagacat tggtagtgcc cctgccctgg gtcccactcc 4900tgccccaccc cacccttgtc cctggccatt gcctggtggt ctagaaacac 4950 ttaaaacttgaagtagtgac acctacctgc ggtcatattg tagagagatg 5000 ctcagtgtta aaactgaaacacacaaacac acacacacac acatttttct 5050 cttgtagatt ttaatttttt aagtgggaaagaactcacct tgccttcctc 5100 ccccaaatgt gcaacctgta aaaggtctct ccacaccaggggccaggatc 5150 cagttccctc atctctggca ggaaagatcc acagcttttc ctccatgtct5200 gttactcact ttcagcagtc cgggtaaaat ctgtggatca gggttaaaaa 5250agcaccgtgg agaatggccc tcttcaggaa agaaaaataa gcaaatgaat 5300 ggtccacctaggggttcagt aaagaaagaa atgtgttaac tgagcctgaa 5350 tcccttctgg gaagtaataatgaccattga caactaagaa gtagacacca 5400 tgctaaagac ttacatacaa tctccttgaatcttctcaat agcccattga 5450 cttagaaact gttactttcc cattttacac acagtgaaactgaggctcag 5500 atataaagga aaggtactgg cttgaagtca caaccacgac aggagtaagg5550 atttggaata aggatttggt cctgttttct ggaccaaatc cttactctgg 5600ctctgcttac actttctctc catcaccaaa tccttactcc aaatccagaa 5650 gtcagagccaactcccatct tggttctgac ccaaatcctg ctctggactc 5700 tggagaggag attgaaatataattgcaccc tcatacacat ttaggaaatg 5750 gttaagaagt gtaaactgaa cccttatccttgtcttcaat cttcctccct 5800 gtagacatct atcttattat ggttattatt cagaaaacccagggatacag 5850 gtttgtcttc ttactttgat aactcttctt agtttaaaat aataataata5900 acacatcttt ggtcatctat gtcacacaaa aattttcctt tgtttgcggg 5950gggctgggga tgcagtgttt tttggggggt cttggtttat gctccctgcc 6000 cttgagcccctcagccgttt gccctgcccc cacctcggct ccatggtggg 6050 agggggctct ggtcttttctaaagtgggcg gtttgtcttt tgatctttcc 6100 cttttggatg tgcgtgtgtg tctgcgtgtgccatgtgcgt ggcacgcata 6150 tgagtgtgtg tgcgtgtgaa cggctttggg tcctgctggttttgctgtga 6200 gctgcagtgt tctgtgggtc tgtggtatct gacactgtgg acattaatgt6250 acttcttgga cattttaata aattttttaa cagttcaaaa aaaaaaaaaa 6300aaaaaaaaaa 6310 27 4577 DNA Homo Sapien 27 actagagatg gcgggcgggctgctctgaag agacctcggc ggcggcggag 50 gaggagagaa gcgcagcgcc gcgccgcgccggggcccatg tggggaggag 100 tcggagtcgc tgttgccgcc gccgcctgta gctgctggacccgagtggga 150 gtgaggggga aacggcagga tgaagttcgc cgagcacctc tccgcgcaca200 tcactcccga gtggaggaag caatacatcc agtatgaggc tttcaaggat 250atgctgtatt cagctcagga ccaggcacct tctgtggaag ttacagatga 300 ggacacagtaaagaggtatt ttgccaagtt tgaagagaag tttttccaaa 350 cctgtgaaaa agaacttgccaaaatcaaca cattttattc agagaagctc 400 gcagaggctc agcgcaggtt tgctacacttcagaatgagc ttcagtcatc 450 actggatgca cagaaagaaa gcactggtgt tactacgctgcgacaacgca 500 gaaagccagt cttccacttg tcccatgagg aacgtgtcca acatagaaat550 attaaagacc ttaaactggc cttcagtgag ttctacctca gtctaatcct 600gctgcagaac tatcagaatc tgaattttac agggtttcga aaaatcctga 650 aaaagcatgacaagatcctg gaaacatctc gtggagcaga ttggcgagtg 700 gctcacgtag aggtggccccattttataca tgcaagaaaa tcaaccagct 750 tatctctgaa actgaggctg tagtgaccaatgaacttgaa gatggtgaca 800 gacaaaaggc tatgaagcgt ttacgtgtcc cccctttgggagctgctcag 850 cctgcaccag catggactac ttttagagtt ggcctatttt gtggaatatt900 cattgtactg aatattaccc ttgtgcttgc cgctgtattt aaacttgaaa 950cagatagaag tatatggccc ttgataagaa tctatcgggg tggctttctt 1000 ctgattgaattcctttttct actgggcatc aacacgtatg gttggagaca 1050 ggctggagta aaccatgtactcatctttga acttaatccg agaagcaatt 1100 tgtctcatca acatctcttt gagattgctggattcctcgg gatattgtgg 1150 tgcctgagcc ttctggcatg cttctttgct ccaattagtgtcatccccac 1200 atatgtgtat ccacttgccc tttatggatt tatggttttc ttccttatca1250 accccaccaa aactttctac tataaatccc ggttttggct gcttaaactg 1300ctgtttcgag tatttacagc ccccttccat aaggtaggct ttgctgattt 1350 ctggctggcggatcagctga acagcctgtc agtgatactg atggacctgg 1400 aatatatgat ctgcttctacagtttggagc tcaaatggga tgaaagtaag 1450 ggcctgttgc caaataattc agaagaatcaggaatttgcc acaaatatac 1500 atatggtgtg cgggccattg ttcagtgcat tcctgcttggcttcgcttca 1550 tccagtgcct gcgccgatat cgagacacaa aaagggcctt tcctcattta1600 gttaatgctg gcaagtactc cacaactttc ttcatggtgg cgtttgcagc 1650cctttacagc actcacaaag aacgaggtca ctcggacact atggtgttct 1700 tttacctgtggattgtcttt tatatcatca gttcctgcta taccctcatc 1750 tgggatctca agatggactggggtctcttc gataagaatg ctggagagaa 1800 cactttcctc cgggaagaga ttgtatacccccaaaaagcc tactactact 1850 gtgccataat agaggatgtg attctgcgct ttgcttggactatccaaatc 1900 tcgattacct ctacaacttt gttgcctcat tctggggaca tcattgctac1950 tgtctttgcc ccacttgagg ttttccggcg atttgtgtgg aacttcttcc 2000gcctggagaa tgaacatctg aataactgtg gtgaattccg tgctgtgcgg 2050 gacatctctgtggcccccct gaacgcagat gatcagactc tcctagaaca 2100 gatgatggac caggatgatggggtacgaaa ccgccagaag aatcggtcat 2150 ggaagtacaa ccagagcata tccctgcgccggcctcgcct cgcttctcaa 2200 tccaaggctc gtgacactaa ggtattgata gaagacacagatgatgaagc 2250 taacacttga attttctgaa gtctagctta acatctttgg ttttcctact2300 ctacaatcct ttcctcgacc aacgcaacct ctagtacctt tccagccgaa 2350aacaggagaa aacacataac acattttccg agctcttccg gatcggatcc 2400 tatggactccaaacaagctc actgtgtttc ttttcttttc ttctggttta 2450 attttaattt tctattttcaaaacaagtat ttacttcatt tgccaatcag 2500 aggatgtttt aagaaacaaa acatagtatcttatggattg tttacaatca 2550 caaggacata gatacctatc aggatgaaga acaggcattgcaaggaccct 2600 ctgatgggac ggtactgaga tatctcggct tccgctcagc ccggttttga2650 atggttgaaa ccggacattg gtttttaaat tttttgtcag tttatgtgga 2700gaattttttt ctttccttca tacccagcgc aaaggcactg gccgcacttg 2750 caggaaaagtgcaacttaaa gcagtacctt cattcatgaa gctacttttt 2800 aatttgatgt aacttttcttattttgggaa gggttgctgg gtgggtggga 2850 aatatgatgt atttgttaca catagttttctcattattta tgaaacttaa 2900 ccatacagaa tgatataact cctgtgcaat gaaggtgataacagtaaaag 2950 tgatataact cctgtgcaat gaaggtgata acagtaaaag aaggcagggg3000 aaacttacgt tggatgacat ttatgagggt cagtcccaca tacctctttc 3050aggagacaac ttgcaccagt ttgacctttt cttttctttg tttttatttt 3100 aagccaaagtttcattgcta acttcttaag ttgctgctgc tttagagtcc 3150 tgagcatatc tctcataacaaggaatccca cacttcacac caccggctga 3200 atttcatgga agaggttctg ataatttttttaacttttta aggaacagat 3250 gtggaataca ctggcccata tttcaacctt aacagctgaagctatgcctt 3300 attatgcatc cacatgtatg gtccctgtag cgtgaccttt actagctctg3350 aatcagaaga cagagctatt tcagaggctc tgtgtgccct cactagatag 3400tttttcttct gggttcaacc actttagcca gaatttgatc aaattaaaag 3450 tctgtcatggggaaactata tttttgagca catggaacaa attatacttc 3500 ctcattcata ttatgttgatacaaaagacc ttggcagcca tttctcccag 3550 cagttttaaa ggatgaacat tggatttcatgccatcccat agaaaacctg 3600 ttttaaaatt ttagggatct ttacttggtc atacatgaaaagtacactgc 3650 ttagaaatta tagactatta tgatctgtcc acagtgccca ttgtcacttc3700 tttgtctcat ttcttccctt tgttccttag tcatccaaat aagcctgaaa 3750accataagag atattacttt attgaatatg gttggcatta aatttagcat 3800 ttcattatctaacaaaatta atataaattc caggacatgg taaaatgtgt 3850 tttaataacc cccagacccaaatgaaaatt tcaaagtcaa taccagcaga 3900 ttcatgaaag taaatttagt cctataattttcagcttaat tataaacaaa 3950 ggaacaaata agtggaaggg cagctattac cattcgcttagtcaaaacat 4000 tcggttactg ccctttaata cactcctatc atcagcactt ccaccatgta4050 ttacaagtct tgacccatcc ctgtcgtaac tccagtaaaa gttactgtta 4100ctagaaaatt tttatcaatt aactgacaaa tagtttcttt ttaaagtagt 4150 ttcttccatctttattctga ctagcttcca aaatgtgttc cctttttgaa 4200 tcgaggtttt tttgttttgttttgttttct gaaaaaatca tacaactttg 4250 tgcttctatt gcttttttgt gttttgttaagcatgtccct tggcccaaat 4300 ggaagaggaa atgtttaatt aatgcttttt agtttaaataaattgaatca 4350 tttataataa tcagtgttaa caatttagtg acccttggta ggttaaaggt4400 tgcattattt atacttgaga tttttttccc ctaactattc tgttttttgt 4450actttaaaac tatgggggaa atatcactgg tctgtcaaga aacagcagta 4500 attattactgagttaaattg aaaagtccag tggaccaggc atttcttata 4550 taaataaaat tggtggtactaatgtgt 4577 28 2203 DNA Homo Sapien 28 cccttgctgg acccgagtgg gagtgagggggaaacggcag gatgaagttc 50 gccgagcacc tctccgcgca catcactccc gagtggaggaagcaatacat 100 ccagtatgag gctttcaagg atatgctgta ttcagctcag gaccaggcac150 cttctgtgga agttacagat gaggacacag taaagaggta ttttgccaag 200tttgaagaga agtttttcca aacctgtgaa aaagaacttg ccaaaatcaa 250 cacattttattcagagaagc tcgcagaggc tcagcgcagg tttgctacac 300 ttcagaatga gcttcagtcatcactggatg cacagaaaga aagcactggt 350 gttactacgc tgcgacaacg cagaaagccagtcttccact tgtcccatga 400 ggaacgtgtc caacatagaa atattaaaga ccttaaactggccttcagtg 450 agttctacct cagtctaatc ctgctgcaga actatcagaa tctgaatttt500 acagggtttc gaaaaatcct gaaaaagcat gacaagatcc tggaaacatc 550tcgtggagca gattggcgag tggctcacgt agaggtggcc ccattttata 600 catgcaagaaaatcaaccag cttatctctg aaactgaggc tgtagtgacc 650 aatgaacttg aagatggtgacagacaaaag gctatgaagc gtttacgtgt 700 cccccctttg ggagctgctc agcctgcaccagcatggact acttttagag 750 ttggcctatt ttgtggaata ttcattgtac tgaatattacccttgtgctt 800 gccgctgtat ttaaacttga aacagataga agtatatggc ccttgataag850 aatctatcgg ggtggctttc ttctgattga attccttttt ctactgggca 900tcaacacgta tggttggaga caggctggag taaaccatgt actcatcttt 950 gaacttaatccgagaagcaa tttgtctcat caacatctct ttgagattgc 1000 tggattcctc gggatattgtggtgcctgag ccttctggca tgcttctttg 1050 ctccaattag tgtcatcccc acatatgtgtatccacttgc cctttatgga 1100 tttatggttt tcttccttat caaccccacc aaaactttctactataaatc 1150 ccggttttgg ctgcttaaac tgctgtttcg agtatttaca gcccccttcc1200 ataaggtagg ctttgctgat ttctggctgg cggatcagct gaacagcctg 1250tcagtgatac tgatggacct ggaatatatg atctgcttct acagtttgga 1300 gctcaaatgggatgaaagta agggcctgtt gccaaataat tcagaagaat 1350 caggaatttg ccacaaatatacatatggtg tgcgggccat tgttcagtgc 1400 attcctgctt ggcttcgctt catccagtgcctgcgccgat atcgagacac 1450 aaaaagggcc tttcctcatt tagttaatgc tggcaaatactccacaactt 1500 tcttcatggt gacgtttgca gccctttaca gcactcacaa agaacgaggt1550 cactcggaca ctatggtgtt cttttacctg tggattgtct tttatatcat 1600cagttcctgc tataccctca tctgggatct caagatggac tggggtctct 1650 tcgataagaatgctggagag aacactttcc tccgggaaga gattgtatac 1700 ccccaaaaag cctactactactgtgccata atagaggatg tgattctgcg 1750 ctttgcttgg actatccaaa tctcgattacctctacaact ttgttgcctc 1800 attctgggga catcattgct actgtctttg ccccacttgaggttttccgg 1850 cgatttgtgt ggaacttctt ccgcctggag aatgaacatc tgaataactg1900 tggtgaattc cgtgctgtgc gggacatctc tgtggccccc ctgaacgcag 1950atgatcagac tctcctagaa cagatgatgg accaggatga tggggtacga 2000 aaccgccagaagaatcggtc atggaagtac aaccagagca tatccctgcg 2050 ccggcctcgc ctcgcttctcaatccaaggc tcgtgacact aaggtattga 2100 tagaagacac agatgatgaa gctaacacttgaattttctg aagtctagct 2150 taacatcttt ggttttccta ctctacaatc ctttcctcgaccaacgcaag 2200 ggc 2203 29 3162 DNA Homo Sapien 29 gcgccctagccctctttcgg ggatactggc cgaccccctc ttccttttcc 50 cctttagtga aggcctcccccgtcgccgcg cggcttcccg gagccgactg 100 cagactccct cagcccggtg ttccccgcgtccggacgccg aggtcgcggc 150 ttcgcagaaa ctcgggcccc tccatccgcc ctcagaaaagggagcgatgt 200 tgatctcagg aagcacaaag ggaccttcct agctctgact gaaccacgga250 gctcaccctg gacagtatca ctccgtggag gaagactgtg agactgtggc 300tggaagccag attgtagcca cacatccgcc cctgccctac cccagagccc 350 tggagcagcaactggctgca gatcacagac acagtgagga tatgagtgta 400 ggggtgagca cctcagcccctctttcccca acctcgggca caagcgtggg 450 catgtctacc ttctccatca tggactatgtggtgttcgtc ctgctgctgg 500 ttctctctct tgccattggg ctctaccatg cttgtcgtggctggggccgg 550 catactgttg gtgagctgct gatggcggac cgcaaaatgg gctgccttcc600 ggtggcactg tccctgctgg ccaccttcca gtcagccgtg gccatcctgg 650gtgtgccgtc agagatctac cgatttggga cccaatattg gttcctgggc 700 tgctgctactttctggggct gctgatacct gcacacatct tcatccccgt 750 tttctaccgc ctgcatctcaccagtgccta tgagtacctg gagcttcgat 800 tcaataaaac tgtgcgagtg tgtggaactgtgaccttcat ctttcagatg 850 gtgatctaca tgggagttgt gctctatgct ccgtcattggctctcaatgc 900 agtgactggc tttgatctgt ggctgtccgt gctggccctg ggcattgtct950 gtaccgtcta tacagctctg ggtgggctga aggccgtcat ctggacagat 1000gtgttccaga cactggtcat gttcctcggg cagctggcag ttatcatcgt 1050 ggggtcagccaaggtgggcg gcttggggcg tgtgtgggcc gtggcttccc 1100 agcacggccg catctctgggtttgagctgg atccagaccc ctttgtgcgg 1150 cacaccttct ggaccttggc cttcgggggtgtcttcatga tgctctcctt 1200 atacggggtg aaccaggctc aggtgcagcg gtacctcagttcccgcacgg 1250 agaaggctgc tgtgctctcc tgttatgcag tgttcccctt ccagcaggtg1300 tccctctgcg tgggctgcct cattggcctg gtcatgttcg cgtattacca 1350ggagtatccc atgagcattc agcaggctca ggcagcccca gaccagttcg 1400 tcctgtactttgtgatggat ctcctgaagg gcctgccagg cctgccaggg 1450 ctcttcattg cctgcctcttcagcggctct ctcagcacta tatcctctgc 1500 ttttaattca ttggcaactg ttacgatggaagacctgatt cgaccttggt 1550 tccctgagtt ctctgaagcc cgggccatca tgctttccagaggccttgcc 1600 tttggctatg ggctgctttg tctaggaatg gcctatattt cctcccagat1650 gggacctgtg ctgcaggcag caatcagcat ctttggcatg gttgggggac 1700cgctgctggg actcttctgc cttggaatgt tctttccatg tgctaaccct 1750 cctggtgctgttgtgggcct gttggctggg ctcgtcatgg ccttctggat 1800 tggcatcggg agcatcgtgaccagcatggg cttcagcatg ccaccctctc 1850 cctctaatgg gtccagcttc tccctgcccaccaatctaac cgttgccact 1900 gtgaccacac tgatgccctt gactaccttc tccaagcccacagggctgca 1950 gcggttctat tccttgtctt acttatggta cagtgctcac aactccacca2000 cagtgattgt ggtgggcctg attgtcagtc tactcactgg gagaatgcga 2050ggccggtccc tgaaccctgc aaccatttac ccagtgttgc caaagctcct 2100 gtccctccttccgttgtcct gtcagaagcg gctccactgc aggagctacg 2150 gccaggacca cctcgacactggcctgtttc ctgagaagcc gaggaatggt 2200 gtgctggggg acagcagaga caaggaggccatggccctgg atggcacagc 2250 ctatcagggg agcagctcca cctgcatcct ccaggagacctccctgtgat 2300 gttgactcag gaccccgcct ctgtcctcac tgtgccaggc catagccaga2350 ggccaccctg tagtacaggg atgagtcttg gtgtgttctg cagggacagg 2400cctggatgat ctagctcata ccaaaggacc ttgttctgag aggttcttgc 2450 ctgcaggagaagctgtcaca tctcaagcat gtgaggcacc gtttttctcg 2500 tcgcttgcca atctgttttttaaaggatca ggctcgtagg gagcaggatc 2550 atgccagaaa tagggatgga agtgcatcctctgggaaaaa gataatggct 2600 tctgattcaa catagccata gtcctttgaa gtaagtggctagaaacagca 2650 ctctggttat aattgcccca gggcctgatt caggactgac tctccaccat2700 aaaactggaa gctgcttccc ctgtagtccc catttcagta ccagttctgc 2750cagccacagt gagcccctat tattactttc agattgtctg tgacactcaa 2800 gcccctctcatttttatctg tctacctcca ttctgaagag ggaggttttg 2850 gtgtccctgg tcctctgggaatagaagatc catttgtctt tgtgtagagc 2900 aagcacgttt tccacctcac tgtctccatcctccacctct gagatggaca 2950 cttaagagac ggggcaaatg tggatccaag aaaccagggccatgaccagg 3000 tccactgtgg agcagccatc tatctacctg actcctgagc caggctgccg3050 tggtgtcatt tctgtcatcc gtgctctgtt tccttttgga gtttcttctc 3100cacattatct ttgttcctgg ggaataaaaa ctaccattgg acctaaaaaa 3150 aaaaaaaaaaaa 3162 30 1432 DNA Homo Sapien 30 gcgggcgccc agtgcaccgg aggaggtgagcgccaggtcg ccttcgcggc 50 ccggggacac aggcagggac gcgggagctg atgcggctggaccggccggg 100 gaaacagtat tttctggaag ggggcccctc tgaagcggtc caggatcctg150 cacatggcgc tgaccggggc ctcagacccc tctgcagagg cagaggccaa 200cggggagaag ccctttctgc tgcgggcatt gcagatcgcg ctggtggtct 250 ccctctactgggtcacctcc atctccatgg tgttccttaa taagtacctg 300 ctggacagcc cctccctgcggctggacacc cccatcttcg tcaccttcta 350 ccagtgcctg gtgaccacgc tgctgtgcaaaggcctcagc gctctggccg 400 cctgctgccc tggtgccgtg gacttcccca gcttgcgcctggacctcagg 450 gtggcccgca gcgtcctgcc cctgtcggtg gtcttcatcg gcatgatcac500 cttcaataac ctctgcctca agtacgtcgg tgtggccttc tacaatgtgg 550gccgctcact caccaccgtc ttcaacgtgc tgctctccta cctgctgctc 600 aagcagaccacctccttcta tgccctgctc acctgcggta tcatcatcgg 650 gggcttctgg cttggtgtggaccaggaggg ggcagaaggc accctgtcgt 700 ggctgggcac cgtcttcggc gtgctggctagcctctgtgt ctcgctcaac 750 gccatctaca ccacgaaggt gctcccggcg gtggacggcagcatctggcg 800 cctgactttc tacaacaacg tcaacgcctg catcctcttc ctgcccctgc850 tcctgctgct cggggagctt caggccctgc gtgaccttgc ccagctgggc 900agtgcccact tctgggggat gatgacgctg ggcggcctgt ttggctttgc 950 catcggctacgtgacaggac tgcagatcaa gttcaccagt ccgctgaccc 1000 acaatgtgtc gggcacggccaaggcctgtg cccagacagt gctggccgtg 1050 ctctactacg aggagaccaa gagcttcctctggtggacga gcaacatgat 1100 ggtgctgggc ggctcctccg cctacacctg ggtcaggggctgggagatga 1150 agaagactcc ggaggagccc agccccaaag acagcgagaa gagcgccatg1200 ggggtgtgag caccacaggc accctggatg gcccggcccc ggggcccgta 1250cacaggcggg gccagcacag tagtgaaggc ggtctcctgg accccagaag 1300 cgtgctgtggtgtggactgg gtgctactta tagacccaat cagaatacgg 1350 tggttgagaa ggaaccagtgtttacaagta atatcagaaa gttgaaggaa 1400 ccagtgttta caagtaatac cagaaagttgcc 1432 31 1094 DNA Homo Sapien 31 gcccttatcc tgcacatggc gctgaccggggcctcagacc cctctgcaga 50 ggcagaggcc aacggggaga agccctttct gctgcgggcattgcagatcg 100 cgctggtggt ctccctctac tgggtcacct ccatctccat ggtgttcctt150 aataagtacc tgctggacag cccctccctg cggctggaca cccccatctt 200cgtcaccttc taccagtgcc tggtgaccac gctgctgtgc aaaggcctca 250 gcgctctggccgcctgctgc cctggtgccg tggacttccc cagcttgcgc 300 ctggacctca gggtggcccgcagcgtcctg cccctgtcgg tggtcttcat 350 cggcatgatc accttcaata acctctgcctcaagtacgtc ggtgtggcct 400 tctacaatgt gggccgctca ctcaccaccg tcttcaacgtgctgctctcc 450 tacctgctgc tcaagcagac cacctccttc tatgccctgc tcacctgcgg500 tatcatcatc gggggcttct ggcttggtgt ggaccaggag ggggcagaag 550gcaccctgtc gtggctgggc accgtcttcg gcgtgctggc tagcctctgt 600 gtctcgctcaacgccatcta caccacgaag gtgctcccgg cggtggacgg 650 cagcatctgg cgcctgactttctacaacaa cgtcaacgcc tgcatcctct 700 tcctgcccct gctcctgctg ctcggggagcttcaggccct gcgtgacttt 750 gcccagctgg gcagtgccca cttctggggg atgatgacgctgggcggcct 800 gtttggcttt gccatcggct acgtgacagg actgcagatc aagttcacca850 gtccgctgac ccacaatgtg tcgggcacgg ccaaggcctg tgcccagaca 900gtgctggccg tgctctacta cgaggagacc aagagcttcc tctggtggac 950 gagcaacatgatggtgctgg gcggctcctc cgcctacacc tgggtcaggg 1000 gctgggagat gaagaagactccggaggagc ccagccccaa agacagcgag 1050 aagagcgcca tgggggtgtg agcaccacaggcaccctgaa gggc 1094 32 900 DNA Homo Sapien 32 ccgagcgcgg ggcaccgggggcctcctgta taggcgggca ccatgggctc 50 ctgctccggc cgctgcgcgc tcgtcgtcctctgcgctttt cagctggtcg 100 ccgccctgga gaggcaggtg tttgacttcc tgggctaccagtgggcgccc 150 atcctggcca actttgtcca catcatcatc gtcatcctgg gactcttcgg200 caccatccag taccggctgc gctacgtcat ggtgtacacg ctgtgggcag 250ccgtctgggt cacctggaac gtcttcatca tctgcttcta cctggaagtc 300 ggtggcctcttacaggacag cgagctactg accttcagcc tctcccggca 350 tcgctcctgg tggcgtgagcgctggccagg ctgtctgcat gaggaggtgc 400 cagcagtggg cctcggggcc ccccatggccaggccctggt gtcaggtgct 450 ggctgtgccc tggagcccag ctatgtggag gccctacacagtggcctgca 500 gatcctgatc gcgcttctgg gctttgtctg tggctgccag gtggtcagcg550 tgtttacgga ggaagaggac agctttgatt tcattggtgg atttgatcca 600tttcctctct accatgtcaa tgaaaagcca tccagtctct tgtccaagca 650 ggtgtacttgcctgcgtaag tgaggaaaca gctgatcctg ctcctgtggc 700 ctccagcctc agcgaccgaccagtgacaat gacaggagct cccaggcctt 750 gggacgcgcc cccacccagc accccccaggcggccggcag cacctgccct 800 gggttctaag tactggacac cagccagggc ggcagggcagtgccacggct 850 ggctgcagcg tcaagagagt ttgtaatttc ctttctctta aaaaaaaaaa900 33 666 DNA Homo Sapien 33 ctcctgtata ggcgggcacc atgggctcctgctccggccg ctgcgcgctc 50 gtcgtcctct gcgcttttca gctggtcgcc gccctggagaggcaggtgtt 100 tgacttcctg ggctaccagt gggcgcccat cctggccaac tttgtccaca150 tcatcatcgt catcctggga ctcttcggca ccatccagta ccggctgcgc 200tatgtcatgg tgtacacgct gtgggcagcc gtctgggtca cctggaacgt 250 cttcatcatctgcttctacc tggaagtcgg tggcctctta aaggacagcg 300 agctactgac cttcagcctctcccggcatc gctcctggtg gcgtgagcgc 350 tggccaggct gtctgcatga ggaggtgccagcagtgggcc tcggggcccc 400 ccatggccag gccctggtgt caggtgctgg ctgtgccctggagcccagct 450 atgtggaggc cctacacagt tgcctgcaga tcctgatcgc gcttctgggc500 tttgtctgtg gctgccaggt ggtcagcgtg tttacggagg aagaggacag 550ctttgatttc attggtggat ttgatccatt tcctctctac catgtcaatg 600 aaaagccatccagtctcttg tccaagcagg tgtacttgcc tgcgtaagtg 650 aggaaacagc tgatcc 666 34582 DNA Homo sapien 34 ctcctgtata ggcgggcacc atgggctcct gctccggccgctgcgcgctc 50 gtcgtcctct gcgcttttca gctggtcgcc gccctggaga ggcaggtgtt 100tgacttcctg ggctaccagt gggcgcccat cctggccaac tttgtccaca 150 tcatcatcgtcatcctggga ctcttcggca ccatccagta ccggctgcgc 200 tatgtcatgg tgtacacgctgtgggcagcc gtctgggtca cctggaacgt 250 cttcatcatc tgcttctacc tggaagtcggtggcctctta aaggacagcg 300 agctactgac cttcagcctc tcccggcatc gctcctggtggcgtgagcgc 350 tggccaggct gtctgcatga ggaggtgcca gcagtgggcc tcggggcccc400 ccatggccag gccctggtgt caggtgctgg ctgtgccctg gagcccagct 450atgtggaggc cctacacagt tgcctgcaga tcctgatcgc gcttctgggc 500 tttgtctgtggctgccaggt ggtcagcgtg tttacggagg aagaggacag 550 ctgcctgcgt aagtgaggaaacagctgatc ca 582 35 582 DNA Homo Sapien 35 ctcctgtata ggcgggcaccatgggctcct gctccggccg ctgcgcgctc 50 gtcgtcctct gcgcttttca gctggtcgccgccctggaga ggcaggtgtt 100 tgacttcctg ggctaccagt gggcgcccat cctggccaactttgtccaca 150 tcatcatcgt catcctggga ctcttcggca ccatccagta ccggctgcgc200 tacgtcatgg tgtacacgct gtgggcagcc gtctgggtca cctggaacgt 250cttcatcatc tgcttctacc tggaagtcgg tggcctctta caggacagcg 300 agctactgaccttcagcctc tcccggcatc gctcctggtg gcgtgagcgc 350 tggccaggct gtctgcatgaggaggtgcca gcagtgggcc tcggggcccc 400 ccatggccag gccctggtgt caggtgctggctgtgccctg gagcccagct 450 atgtggaggc cctacacagt ggcctgcaga tcctgatcgcgcttctgggc 500 tttgtctgtg gctgccaggt ggtcagcgtg tttacggagg aagaggacag550 ctgcctgcgt aagtgaggaa acagctgatc ca 582 36 1546 DNA Homo sapien 36gcatggaaag tctttatttg agccccttag ctgatgtgga atcagaagag 50 caaaaaggtcatcttcagag tggcctgggc tgggtccttt tctctccagg 100 atagaaaagt ggtggtcactttatccctag tagacatgct gctgggcttt 150 atcgccccag cattcccatc ccctccagagccccttgtca ctccagacca 200 gcgagtgtgg gcctttatct ggactctgct tcctccctggggacaccagg 250 tcttggagca agagaacttg gcaggctctc cccatggcag tcttattcct300 cctcctgttc ctatgtggaa ctccccaggc tgcagacaac atgcaggcca 350tctatgtggc cttgggggag gcagtagagc tgccatgtcc ctcaccacct 400 actctacatggggacgaaca cctgtcatgg ttctgcagcc ctgcagcagg 450 ctccttcacc accctggtagcccaagtcca agtgggcagg ccagccccag 500 accctggaaa accaggaagg gaatccaggctcagactgct ggggaactat 550 tctttgtggt tggagggatc caaagaggaa gatgccgggcggtactggtg 600 cgctgtgcta ggtcagcacc acaactacca gaactggagg gtgtacgacg650 tcttggtgct caaaggatcc cagttatctg caagggctgc agatggatcc 700ccctgcaatg tcctcctgtg ctctgtggtc cccagcagac gcatggactc 750 tgtgacctggcaggaaggga agggtcccgt gaggggccgt gttcagtcct 800 tctggggcag tgaggctgccctgctcttgg tgtgtcctgg ggaggggctt 850 tctgagccca ggagccgaag accaagaatcatccgctgcc tcatgactca 900 caacaaaggg gtcagcttta gcctggcagc ctccatcgatgcttctcctg 950 ccctctgtgc cccttccacg ggctgggaca tgccttggat tctgatgctg1000 ctgctcacaa tgggccaggg agttgtcatc ctggccctca gcatcgtgct 1050ctggaggcag agggtccgtg gggctccagg cagaggaaac cgaatgcggt 1100 gctacaactgtggtggaagc cccagcagtt cttgcaaaga ggccgtgacc 1150 acctgtggcg agggcagaccccagccaggc ctggaacaga tcaagctacc 1200 tggaaacccc ccagtgacct tgattcaccaacatccagcc tgcgtcgcag 1250 cccatcattg caatcaagtg gagacagagt cggtgggagacgtgacttat 1300 ccagcccaca gggactgcta cctgggagac ctgtgcaaca gcgccgtggc1350 aagccatgtg gcccctgcag gcattttggc tgcagcagct accgccctga 1400cctgtctctt gccaggactg tggagcggat agggggagta ggagtagaga 1450 agggaacaagggagcaaggg aacaagggac atctgaacat ctaatgtgag 1500 aagagaaaca tccttctgtgagtcattaaa atctatgaac cactct 1546 37 4619 DNA Homo Sapien 37 ctttagagaaaggaagggcc aaaactacga cttggctttc tgaaacggaa 50 gcataaatgt tcttttcctccatttgtctg gatctgagaa cctgcatttg 100 gtattagcta gtggaagcag tatgtatggttgaagtgcat tgctgcagct 150 ggtagcatga gtggtggcca ccagctgcag ctggctgccctctggccctg 200 gctgctgatg gctaccctgc aggcaggctt tggacgcaca ggactggtac250 tggcagcagc ggtggagtct gaaagatcag cagaacagaa agctgttatc 300agagtgatcc ccttgaaaat ggaccccaca ggaaaactga atctcacttt 350 ggaaggtgtgtttgctggtg ttgctgaaat aactccagca gaaggaaaat 400 taatgcagtc ccacccactgtacctgtgca atgccagtga tgacgacaat 450 ctggagcctg gattcatcag catcgtcaagctggagagtc ctcgacgggc 500 cccccgcccc tgcctgtcac tggctagcaa ggctcggatggcgggtgagc 550 gaggagccag tgctgtcctc tttgacatca ctgaggatcg agctgctgct600 gagcagctgc agcagccgct ggggctgacc tggccagtgg tgttgatctg 650gggtaatgac gctgagaagc tgatggagtt tgtgtacaag aaccaaaagg 700 cccatgtgaggattgagctg aaggagcccc cggcctggcc agattatgat 750 gtgtggatcc taatgacagtggtgggcacc atctttgtga tcatcctggc 800 ttcggtgctg cgcatccggt gccgcccccgccacagcagg ccggatccgc 850 ttcagcagag aacagcctgg gccatcagcc agctggccaccaggaggtac 900 caggccagct gcaggcaggc ccggggtgag tggccagact cagggagcag950 ctgcagctca gcccctgtgt gtgccatctg tctggaggag ttctctgagg 1000ggcaggagct acgggtcatt tcctgcctcc atgagttcca tcgtaactgt 1050 gtggacccctggttacatca gcatcggact tgccccctct gcgtgttcaa 1100 catcacagag ggagattcattttcccagtc cctgggaccc tctcgatctt 1150 accaagaacc aggtcgaaga ctccacctcattcgccagca tcccggccat 1200 gcccactacc acctccctgc tgcctacctg ttgggcccttcccggagtgc 1250 agtggctcgg cccccacgac ctggtccctt cctgccatcc caggagccag1300 gcatgggccc tcggcatcac cgcttcccca gagctgcaca tccccgggct 1350ccaggagagc agcagcgcct ggcaggagcc cagcacccct atgcacaagg 1400 ctggggaatgagccacctcc aatccacctc acagcaccct gctgcttgcc 1450 cagtgcccct acgccgggccaggccccctg acagcagtgg atctggagaa 1500 agctattgca cagaacgcag tgggtacctggcagatgggc cagccagtga 1550 ctccagctca gggccctgtc atggctcttc cagtgactctgtggtcaact 1600 gcacggacat cagcctacag ggggtccatg gcagcagttc tactttctgc1650 agctccctaa gcagtgactt tgacccccta gtgtactgca gccctaaagg 1700ggatccccag cgagtggaca tgcagcctag tgtgacctct cggcctcgtt 1750 ccttggactcggtggtgccc acaggggaaa cccaggtttc cagccatgtc 1800 cactaccacc gccaccggcaccaccactac aaaaagcggt tccagtggca 1850 tggcaggaag cctggcccag aaaccggagtcccccagtcc aggcctccta 1900 ttcctcggac acagccccag ccagagccac cttctcctgatcagcaagtc 1950 accggatcca actcagcagc cccttcgggg cggctctcta acccacagtg2000 ccccagggcc ctccctgagc cagcccctgg cccagttgac gcctccagca 2050tctgccccag taccagcagt ctgttcaact tgcaaaaatc cagcctctct 2100 gcccgacacccacagaggaa aaggcggggg ggtccctccg agcccacccc 2150 tggctctcgg ccccaggatgcaactgtgca cccagcttgc cagatttttc 2200 cccattacac ccccagtgtg gcatatccttggtccccaga ggcacacccc 2250 ttgatctgtg gacctccagg cctggacaag aggctgctaccagaaacccc 2300 aggcccctgt tactcaaatt cacagccagt gtggttgtgc ctgactcctc2350 gccagcccct ggaaccacat ccacctgggg aggggccttc tgaatggagt 2400tctgacaccg cagagggcag gccatgccct tatccgcact gccaggtgct 2450 gtcggcccagcctggctcag aggaggaact cgaggagctg tgtgaacagg 2500 ctgtgtgaga tgttcaggcctagctccaac caagagtgtg ctccagatgt 2550 gtttgggccc tacctggcac agagtcctgctcctgggaaa ggaaaggacc 2600 acagcaaaca ccattctttt tgccgtactt cctagaagcactggaagagg 2650 actggtgatg gtggagggtg agagggtgcc gtttcctgct ccagctccag2700 accttgtctg cagaaaacat ctgcagtgca gcaaatccat gtccagccag 2750gcaaccagct gctgcctgtg gcgtgtgtgg gctggatccc ttgaaggctg 2800 agtttttgagggcagaaagc tagctatggg tagccaggtg ttacaaaggt 2850 gctgctcctt ctccaacccctacttggttt ccctcacccc aagcctcatg 2900 ttcataccag ccagtgggtt cagcagaacgcatgacacct tatcacctcc 2950 ctccttgggt gagctctgaa caccagcttt ggcccctccacagtaaggct 3000 gctacatcag gggcaaccct ggctctatca ttttcctttt ttgccaaaag3050 gaccagtagc ataggtgagc cctgagcact aaaaggaggg gtccctgaag 3100ctttcccact atagtgtgga gttctgtccc tgaggtgggt acagcagcct 3150 tggttcctctgggggttgag aataagaata gtggggaggg aaaaactcct 3200 ccttgaagat ttcctgtctcagagtcccag agaggtagaa aggaggaatt 3250 tctgctggac ttcatctggg cagaggaaggatggaatgaa ggtagaaaag 3300 gcagaattac agctgagcgg ggacaacaaa gagttcttctctgggaaaag 3350 ttttgtctta gagcaaggat ggaaaatggg gacaacaaag gaaaagcaaa3400 gtgtgaccct tgggtttgga cagcccagag gcccagctcc ccagtataag 3450ccatacaggc cagggaccca caggagagtg gattagagca caagtctggc 3500 ctcactgagtggacaagagc tgatgggcct catcagggtg acattcaccc 3550 cagggcagcc tgaccactcttggcccctca ggcattatcc catttggaat 3600 gtgaatgtgg tggcaaagtg ggcagaggaccccacctggg aacctttttc 3650 cctcagttag tggggagact agcacctagg tacccacatgggtatttata 3700 tctgaaccag acagacgctt gaatcaggca ctatgttaag aaatatattt3750 atttgctaat atatttatcc acaaatgtgg tctggtcttg tggttttgtt 3800ctgtcgtgac tgtcactcag ggtaacaacg tcatctcttt ctacatcaag 3850 agaagtaaattatttatgtt atcagaggct aggctccgat tcatgaaagg 3900 atagggtaga gtagagggcttggcaataag aactggtttg taagccccta 3950 aaagtgtggc ttagtgagat cagggaaggagaaagcatga ctggattctt 4000 actgtgcttc agtcattatt attatactgt tcacttcacacattatcata 4050 cttcagtgac tyagaccttg ggcaaatact ctgtgcctcg ctttttcagt4100 ccataaaatg ggcctactta atagttgttg caggacttac atgagataat 4150agagtgtaga aaatatgttc caaagtggaa agttttattc agtgatagaa 4200 aacatccaaacctgtcacag agcccatctg aacacagcat gggaccgcca 4250 acaagaagaa agcccgcccggaagcagctc aatcaggagg ctgggctgga 4300 atgacagcgc agcggggcct gaaactatttatatcccaaa gctcctctca 4350 gataaacaca aatgactgcg ttctgcctgc actcgggctattgcgaggac 4400 agagagctgg tgctccattg gcgtgaagtc tccagggcca gaaggggcct4450 ttgtcgcttc ctcacaaggc acaagttccc cttctgcttc cccgagaaag 4500gtttggtagg ggtggtggtt tagtgcctat agaacaaggc atttcgcttc 4550 ctagacggtgaaatgaaagg gaaaaaaagg acacctaatc tcctacaaat 4600 ggtctttagt aaaggaacc4619 38 3510 DNA Homo Sapien 38 gcagctctgg gggagctcgg agctcccgatcacggcttct tgggggtagc 50 tacggctggg tgtgtagaac ggggccgggg ctggggctgggtcccctagt 100 ggagacccaa gtgcgagagg caagaactct gcagcttcct gccttctggg150 tcagttcctt attcaagtct gcagccggct cccagggaga tctcggtgga 200acttcagaaa cgctgggcag tctgcctttc aaccatgccc ctgtccctgg 250 gagccgagatgtgggggcct gaggcctggc tgctgctgct gctactgctg 300 gcatcattta caggccggtgccccgcgggt gagctggaga cctcagacgt 350 ggtaactgtg gtgctgggcc aggacgcaaaactgccctgc ttctaccgag 400 gggactccgg cgagcaagtg gggcaagtgg catgggctcgggtggacgcg 450 ggcgaaggcg cccaggaact agcgctactg cactccaaat acgggcttca500 tgtgagcccg gcttacgagg gccgcgtgga gcagccgccg cccccacgca 550accccctgga cggctcagtg ctcctgcgca acgcagtgca ggcggatgag 600 ggcgagtacgagtgccgggt cagcaccttc cccgccggca gcttccaggc 650 gcggctgcgg ctccgagtgctggtgcctcc cctgccctca ctgaatcctg 700 gtccagcact agaagagggc cagggcctgaccctggcagc ctcctgcaca 750 gctgagggca gcccagcccc cagcgtgacc tgggacacggaggtcaaagg 800 cacaacgtcc agccgttcct tcaagcactc ccgctctgct gccgtcacct850 cagagttcca cttggtgcct agccgcagca tgaatgggca gccactgact 900tgtgtggtgt cccatcctgg cctgctccag gaccaaagga tcacccacat 950 cctccacgtgtccttccttg ctgaggcctc tgtgaggggc cttgaagacc 1000 aaaatctgtg gcacattggcagagaaggag ctatgctcaa gtgcctgagt 1050 gaagggcagc cccctccctc atacaactggacacggctgg atgggcctct 1100 gcccagtggg gtacgagtgg atggggacac tttgggctttcccccactga 1150 ccactgagca cagcggcatc tacgtctgcc atgtcagcaa tgagttctcc1200 tcaagggatt ctcaggtcac tgtggatgtt cttgaccccc aggaagactc 1250tgggaagcag gtggacctag tgtcagcctc ggtggtggtg gtgggtgtga 1300 tcgccgcactcttgttctgc cttctggtgg tggtggtggt gctcatgtcc 1350 cgataccatc ggcgcaaggcccagcagatg acccagaaat atgaggagga 1400 gctgaccctg accagggaga actccatccggaggctgcat tcccatcaca 1450 cggaccccag gagccagccg gaggagagtg tagggctgagagccgagggc 1500 caccctgata gtctcaagga caacagtagc tgctctgtga tgagtgaaga1550 gcccgagggc cgcagttact ccacgctgac cacggtgagg gagatagaaa 1600cacagactga actgctgtct ccaggctctg ggcgggccga ggaggaggaa 1650 gatcaggatgaaggcatcaa acaggccatg aaccattttg ttcaggagaa 1700 tgggacccta cgggccaagcccacgggcaa tggcatctac atcaatgggc 1750 ggggacacct ggtctgaccc aggcctgcctcccttcccta ggcctggctc 1800 cttctgttga catgggagat tttagctcat cttgggggcctccttaaaca 1850 cccccatttc ttgcggaaga tgctccccat cccactgact gcttgacctt1900 tacctccaac ccttctgttc atcgggaggg ctccaccaat tgagtctctc 1950ccaccatgca tgcaggtcac tgtgtgtgtg catgtgtgcc tgtgtgagtg 2000 ttgactgactgtgtgtgtgt ggaggggtga ctgtccgtgg aggggtgact 2050 gtgtccgtgg tgtgtattatgctgtcatat cagagtcaag tgaactgtgg 2100 tgtatgtgcc acgggatttg agtggttgcgtgggcaacac tgtcagggtt 2150 tggcgtgtgt gtcatgtggc tgtgtgtgac ctctgcctgaaaaagcaggt 2200 attttctcag accccagagc agtattaatg atgcagaggt tggaggagag2250 aggtggagac tgtggctcag acccaggtgt gcgggcatag ctggagctgg 2300aatctgcctc cggtgtgagg gaacctgtct cctaccactt cggagccatg 2350 ggggcaagtgtgaagcagcc agtccctggg tcagccagag gcttgaactg 2400 ttacagaagc cctctgccctctggtggcct ctgggcctgc tgcatgtaca 2450 tattttctgt aaatatacat gcgccgggagcttcttgcag gaatactgct 2500 ccgaatcact tttaattttt ttcttttttt tttcttgccctttccattag 2550 ttgtattttt tatttatttt tatttttatt tttttttaga gatggagtct2600 cactatgttg ctcaggctgg ccttgaactc ctgggctcaa gcaatcctcc 2650tgcctcagcc tccctagtag ctgggacttt aagtgtacac cactgtgcct 2700 gctttgaatcctttacgaag agaaaaaaaa aattaaagaa agcctttaga 2750 tttatccaat gtttactactgggattgctt aaagtgaggc ccctccaaca 2800 ccagggggtt aattcctgtg attgtgaaaggggctacttc caaggcatct 2850 tcatgcaggc agccccttgg gagggcacct gagagctggtagagtctgaa 2900 attagggatg tgagcctcgt ggttactgag taaggtaaaa ttgcatccac2950 cattgtttgt gataccttag ggaattgctt ggacctggtg acaagggctc 3000ctgttcaata gtggtgttgg ggagagagag agcagtgatt atagaccgag 3050 agagtaggagttgaggtgag gtgaaggagg tgctgggggt gagaatgtcg 3100 cctttccccc tgggttttggatcactaatt caaggctctt ctggatgttt 3150 ctctgggttg gggctggagt tcaatgaggtttatttttag ctggcccacc 3200 cagatacact cagccagaat acctagattt agtacccaaactcttcttag 3250 tctgaaatct gctggatttc tggcctaagg gagaggctcc catccttcgt3300 tccccagcca gcctaggact tcgaatgtgg agcctgaaga tctaagatcc 3350taacatgtac attttatgta aatatgtgca tatttgtaca taaaatgata 3400 ttctgtttttaaataaacag acaaaacttg aaaaaaaaaa aaaaaaaaaa 3450 aaaaaaaaaa aaaaaaaaaaaaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 3500 aaaaaaaaaa 3510 39 2211 DNA Homosapien 39 ttgggggttt attctcttcc cttctaactt gacagggtct tgctctgtca 50ttcaggcaag agtgcagtag tgtgatcact tcttactgcc gcctcaagct 100 tccagcctcaactcaagcaa tcctcccacc tcagccaccc aagtggctgg 150 gactacagat taagaatgacccaaaataaa ttaaagcttt gttccaaagc 200 caatgtgtat actgaagtgc ctgatggaggatggggctgg gcggtagctg 250 tttcattttt cttcgttgaa gtcttcacct acggcatcatcaagacattt 300 ggtgtcttct ttaatgactt aatggacagt tttaatgaat ccaatagcag350 gatctcatgg ataatctcaa tctgtgtgtt tgtcttaaca ttttcagctc 400ccctcgccac agtcctgagc aatcgtttcg gacaccgtct ggtagtgatg 450 ttgggggggctacttgtcag caccgggatg gtggccgcct ccttctcaca 500 agaggtttct catatgtacgtcgccatcgg catcatctct ggtctgggat 550 actgctttag ttttctccca actgtaaccatcctatcaca atattttggc 600 aaaagacgtt ccatagtcac tgcagttgct tccacaggagaatgtttcgc 650 tgtgtttgct ttcgcaccag caatcatggc tctgaaggag cgcattggct700 ggagatacag cctcctcttc gtgggcctac tacagttaaa cattgtcatc 750ttcggagcac tgctcagacc catcattatc agaggaccag cgtcaccgaa 800 aatagtcatccaggaaaatc ggaaagaagc gcagtatatg cttgaaaatg 850 agaaaacacg aacctcaatagactccattg actcaggagt agaactaact 900 acctcaccta aaaatgtgcc tactcacactaacctggaac tggagccgaa 950 ggccgacatg cagcaggtcc tggtgaagac cagccccaggccaagcgaaa 1000 agaaagcccc gctattagac ttctccattt tgaaagagaa aagttttatt1050 tgttatgcat tatttggtct ctttgcaaca ctgggattct ttgcaccttc 1100cttgtacatc attcctctgg gcattagtct gggcattgac caggaccgcg 1150 ctgcttttttattatctacg atggccattg cagaagtttt cggaaggatc 1200 ggagctggtt ttgtcctcaacagggagccc attcgtaaga tttacattga 1250 gctcatctgc gtcatcttat tgactgtgtctctgtttgcc tttacttttg 1300 ctactgaatt ctggggtcta atgtcatgca gcatattttttgggtttatg 1350 gttggaacaa taggaggact cacattccac tgcttgctga agatgatgtc1400 gtgggcattg cagaagatgt cttctgcagc tggggtctac atcttcattc 1450agagcatagc aggactggct ggaccgcccc ttgcaggttt gttggtggac 1500 caaagtaagatctacagcag ggccttctac tcctgcgcag ctggcatggc 1550 cctggctgct gtgtgcctcgccctggtgag accgtgtaag atgggactgt 1600 gccagcgtca tcactcaggt gaaacaaaggtagtgagcca tcgtgggaag 1650 actttacagg acatacctga agactttctg gaaatggatcttgcaaaaaa 1700 tgagcacaga gttcacgtgc aaatggagcc ggtatgacac actttcttac1750 aacaacagcc actgtgttgg ctggagaggg atggggtggg cccaacgggg 1800acacaaggag gcagaggagc taacccctct actccacttt caaaactaca 1850 ttttaaagggaatgtgtatg tgaagagcac taccaacatc gcttttgttt 1900 tgttttgttt tgttttaagctttttttttt tgcttgtttt taaagccaaa 1950 acaaaaaaca accaagcact cttccatatataaatctggc tgtattcagt 2000 agcaatacaa gagatatgta gaaagactct ttggttcacattccgatatt 2050 aaaatagtga catgaactgg caaagtggtt ttaaaagctt tcacgtggga2100 taaatgattt tctttttttc ttttctttct tcctatggtc ttgtctgaat 2150aaactactct cctgaataaa acaacatcca acccaggtca ttgaaatgaa 2200 attggccagt c2211 40 685 DNA Homo Sapien 40 gatgtgctcc ttggagctgg tgtgcagtgtcctgactgta agatcaagtc 50 caaacctgtt ttggaattga ggaaacttct cttttgatctcagcccttgg 100 tggtccaggt cttcatgctg ctgtgggtga tattactggt cctggctcct150 gtcagtggac agtttgcaag gacacccagg cccattattt tcctccagcc 200tccatggacc acagtcttcc aaggagagag agtgaccctc acttgcaagg 250 gatttcgcttctactcacca cagaaaacaa aatggtacca tcggtacctt 300 gggaaagaaa tactaagagaaaccccagac aatatccttg aggttcagga 350 atctggagag tacagatgcc aggcccagggctcccctctc agtagccctg 400 tgcacttgga tttttcttca gagatgggat ttcctcatgctgcccaggct 450 aatgttgaac tcctgggctc aagtgatctg ctcacctagg cctctcaaag500 cgctgggatt acagcttcgc tgatcctgca agctccactt tctgtgtttg 550aaggagactc tgtggttctg aggtgccggg caaaggcgga agtaacactg 600 aataatactatttacaagaa tgataatgtc ctggcattcc ttaataaaag 650 aactgacttc caaaaaaaaaaaaaaaaaaa aaaaa 685 41 5392 DNA Homo Sapien 41 aattcactaa tgcattctgctctttttgag agcacagctt ctcagatgtg 50 ctccttggag ctggtgtgca gtgtcctgactgtaagatca agtccaaacc 100 tgttttggaa ttgaggaaac ttctcttttg atctcagcccttggtggtcc 150 aggtcttcat gctgctgtgg gtgatattac tggtcctggc tcctgtcagt200 ggacagtttg caaggacacc caggcccatt attttcctcc agcctccatg 250gaccacagtc ttccaaggag agagagtgac cctcacttgc aagggatttc 300 gcttctactcaccacagaaa acaaaatggt accatcggta cctcgggaaa 350 gaaatactaa gagaaaccccagacaatatc cttgaggttc aggaatctgg 400 agagtacaga tgccaggccc agggctcccctctcagtagc cctgtgcact 450 tggatttttc ttcagcttcg ctgatcctgc aagctccactttctgtgttt 500 gaaggagact ctgtggttct gaggtgccgg gcaaaggcgg aagtaacact550 gaataatact atttacaaga atgataatgt cctggcattc cttaataaaa 600gaactgactt ccatattcct catgcatgtc tcaaggacaa tggtgcatat 650 cgctgtactggatataagga aagttgttgc cctgtttctt ccaatacagt 700 caaaatccaa gtccaagagccatttacacg tccagtgctg agagccagct 750 ccttccagcc catcagcggg aacccagtgaccctgacctg tgagacccag 800 ctctctctag agaggtcaga tgtcccgctc cggttccgcttcttcagaga 850 tgaccagacc ctgggattag gctggagtct ctccccgaat ttccagatta900 ctgccatgtg gagtaaagat tcagggttct actggtgtaa ggcagcaaca 950atgcctcaca gcgtcatatc tgacagcccg agatcctgga tacaggtgca 1000 gatccctgcatctcatcctg tcctcactct cagccctgaa aaggctctga 1050 attttgaggg aaccaaggtgacacttcact gtgaaaccca ggaagattct 1100 ctgcgcactt tgtacaggtt ttatcatgagggtgtccccc tgaggcacaa 1150 gtcagtccgc tgtgaaaggg gagcatccat cagcttctcactgactacag 1200 agaattcagg gaactactac tgcacagctg acaatggcct tggcgccaag1250 cccagtaagg ctgtgagcct ctcagtcact gttcccgtgt ctcatcctgt 1300cctcaacctc agctctcctg aggacctgat ttttgaggga gccaaggtga 1350 cacttcactgtgaagcccag agaggttcac tccccatcct gtaccagttt 1400 catcatgagg atgctgccctggagcgtagg tcggccaact ctgcaggagg 1450 agtggccatc agcttctctc tgactgcagagcattcaggg aactactact 1500 gcacagctga caatggcttt ggcccccagc gcagtaaggcggtgagcctc 1550 tccatcactg tccctgtgtc tcatcctgtc ctcaccctca gctctgctga1600 ggccctgact tttgaaggag ccactgtgac acttcactgt gaagtccaga 1650gaggttcccc acaaatccta taccagtttt atcatgagga catgcccctg 1700 tggagcagctcaacaccctc tgtgggaaga gtgtccttca gcttctctct 1750 gactgaagga cattcagggaattactactg cacagctgac aatggctttg 1800 gtccccagcg cagtgaagtg gtgagcctttttgtcactgt tccagtgtct 1850 cgccccatcc tcaccctcag ggttcccagg gcccaggctgtggtggggga 1900 cctgctggag cttcactgtg aggccccgag aggctctccc ccaatcctgt1950 actggtttta tcatgaggat gtcaccctgg ggagcagctc agccccctct 2000ggaggagaag cttctttcaa cctctctctg actgcagaac attctggaaa 2050 ctactcatgtgaggccaaca atggcctagt ggcccagcac agtgacacaa 2100 tatcactcag tgttatagttccagtatctc gtcccatcct caccttcagg 2150 gctcccaggg cccaggctgt ggtgggggacctgctggagc ttcactgtga 2200 ggccctgaga ggctcctccc caatcctgta ctggttttatcatgaagatg 2250 tcaccctggg taagatctca gccccctctg gaggaggggc ctccttcaac2300 ctctctctga ctacagaaca ttctggaatc tactcctgtg aggcagacaa 2350tggtccggag gcccagcgca gtgagatggt gacactgaaa gttgcagttc 2400 cggtgtctcgcccggtcctc accctcaggg ctcccgggac ccatgctgcg 2450 gtgggggacc tgctggagcttcactgtgag gccctgagag gctctcccct 2500 gatcctgtac cggttttttc atgaggatgtcaccctagga aataggtcgt 2550 ccccctctgg aggagcgtcc ttaaacctct ctctgactgcagagcactct 2600 ggaaactact cctgtgaggc cgacaatggc ctcggggccc agcgcagtga2650 gacagtgaca ctttatatca cagggctgac cgcgaacaga agtggccctt 2700ttgccacagg agtcgccggg ggcctgctca gcatagcagg ccttgctgcg 2750 ggggcactgctgctctactg ctggctctcg agaaaagcag ggagaaagcc 2800 tgcctctgac cccgccaggagccctccaga ctcggactcc caagagccca 2850 cctatcacaa tgtaccagcc tgggaagagctgcaaccagt gtacactaat 2900 gcaaatccta gaggagaaaa tgtggtttac tcagaagtacggatcatcca 2950 agagaaaaag aaacatgcag tggcctctga ccccaggcat ctcaggaaca3000 agggttcccc tatcatctac tctgaagtta aggtggcgtc aaccccggtt 3050tccggatccc tgttcttggc ttcctcagct cctcacagat gagtccacac 3100 gtctctccaactgctgtttc agcctctgca ccccaaagtt ccccttgggg 3150 gagaagcagc attgaagtgggaagatttag gctgccccag accatatcta 3200 ctggcctttg tttcacatgt cctcattctcagtctgacca gaatgcaggg 3250 ccctgctgga ctgtcacctg tttcccagtt aaagccctgactggcaggtt 3300 ttttaatcca gtggcaaggt gctcccactc cagggcccag cacatctcct3350 ggattcctta gtgggcttca gctgtgattg ctgttctgag tactgctctc 3400atcacacccc cacagagggg gtcttaccac acaaagggag agtgggcctt 3450 caggagatgccgggctggcc taacagctca ggtgctccta aactccgaca 3500 cagagttcct gctttgggtggatgcatttc tcaattgtca tcagcctggt 3550 ggggctactg cagtgtgctg ccaaatgggacagcacacag cctgtgcaca 3600 tgggacatgt gatgggtctc cccacggggg ctgcatttcacactcctcca 3650 cctgtctcaa actctaaggt cggcacttga caccaaggta acttctctcc3700 tgctcatgtg tcagtgtcta cctgcccaag taagtggctt tcatacacca 3750agtcccaagt tcttcccatc ctaacagaag taacccagca agtcaaggcc 3800 aggaggaccaggggtgcaga cagaacacat actggaacac aggaggtgct 3850 caattactat ttgactgactgactgaatga atgaatgaat gaggaagaaa 3900 actgtgggta atcaaactgg cataaaatccagtgcactcc ctaggaaatc 3950 cgggaggtat tctggcttcc ctaagaaaca acggaagagaaggagcttgg 4000 atgaggaaac tgttcagcaa gaggaagggc ttctcacact ttcatgtgct4050 tgtggatcac ctgaggatcc tgtgaaaata cagatactga ttcagtgggt 4100ctgtgtagag cctgagactg ccattctaac atgttcccag gggatgctga 4150 tgctgctggccctgggactg cactgcatgc atgtgaagcc ctataggtct 4200 cagcagaggc ccatggagagggaatgtgtg gctctggctg cccagggccc 4250 aactcggttc acacggatcg tgctgctccctggccagcct ttggccacag 4300 caccaccagc tgctgttgct gagagagctt cttctctgtgacatgttggc 4350 tttcatcagc caccctggga agcggaaagt agctgccact atctttgttt4400 ccccacctca ggcctcacac tttcccatga aaagggtgaa tgtatataac 4450ctgagccctc tccattcaga gttgttctcc catctctgag caatgggatg 4500 ttctgttccgcttttatgat atccatcaca tcttatcttg atctttgctc 4550 ccagtggatt gtacagtgatgacttttaag ccccacggcc ctgaaataaa 4600 atccttccaa gggcattgga agctctctccacctgaacca tggcttttca 4650 tgcttccaag tgtcagggcc ttgcccagat agacagggctgactctgctg 4700 ccccaacctt tcaaggagga aaccagacac ctgagacagg agcctgtatg4750 cagcccagtg cagccttgca gaggacaagg ctggaggcat ttgtcatcac 4800tacagatatg caactaaaat agacgtggag caagagaaat gcattcccac 4850 cgaggccgcttttttaggcc tagttgaaag tcaagaagga cagcagcaag 4900 cataggctca ggattaaagaaaaaaatctg ctcacagttt gttctggagg 4950 tcacatcacc aacaaagctc acgccctatgcagttctgag aaggtggagg 5000 caccaggctc aaaagaggaa atttagaatt tctcattgggagagtaaggt 5050 acccccatcc cagaatgata actgcacagt ggcagaacaa actccaccct5100 aatgtgggtg gaccccatcc agtctgttga aggcctgagt gtaacaaaag 5150ggcttattct tcctcaagta agggggaact cctgctttgg gctgggacat 5200 aagtttttctgctttcagac gcaaactgaa aaatggctct tcttgggtct 5250 tgagcttgct ggcatatggactgaaagaaa ctatgctatt ggatctcctg 5300 gatctccagc ttgctgactg cagatcttgagatatgtcag cctctacagt 5350 cacaagagct aattcattct aataaaccaa tctttctgtaaa 5392 42 626 DNA Homo Sapien 42 ggacctggga aggagcatag gacagggcaaggcgggataa ggaggggcac 50 cacagccctt aaggcacgag ggaacctcac tgcgcatgctcctttggtgc 100 ccacctcagt gcgcatgttc actgggcgtc ttcccatcgg ccccttcgcc150 agtgtgggga acgcggcgga gctgtgagcc ggcgactcgg gtccctgagg 200tctggattct ttctccgcta ctgagacacg gcggacacac acaaacacag 250 aaccacacagccagtcccag gagcccagta atggagagcc ccaaaaagaa 300 gaaccagcag ctgaaagtcgggatcctaca cctgggcagc agacagaaga 350 agatcaggat acagctgaga tcccagtgcgcgacatggaa ggtgatctgc 400 aagagctgca tcagtcaaac accggggata aatctggatttgggttccgg 450 cgtcaaggtg aagataatac ctaaagagga acactgtaaa atgccagaag500 caggtgaaga gcaaccacaa gtttaaatga agacaagctg aaacaacgca 550agctggtttt atattagata tttgacttaa actatctcaa taaagttttg 600 cagctttcaccaaaaaaaaa aaaaaa 626 43 1505 DNA Homo Sapien 43 agcggctggc gagccggcgccggccgagct gcgggagccg cggagagcac 50 cagctgtcgc cgcgggagct gctccggccgcaccatgcgg gagctggcca 100 ttgagatcgg ggtgcgagcc ctgctcttcg gagtcttcgtttttacagag 150 tttttggatc cgttccagag agtcatccag ccagaagaga tctggctcta200 taaaaatcct ttggtgcaat cagataacat acctacccgc ctcatgtttg 250caatttcttt cctcacaccc ctggctgtta tttgtgtggt gaaaattatc 300 cggcgaacagacaagactga aattaaggaa gccttcttag cggtgtcctt 350 ggctcttgct ttgaatggagtctgcacaaa cactattaaa ttaatagtgg 400 gaagacctcg cgccgatttc ttttaccgctgctttccaga tggagtgatg 450 aactcggaaa tgcattgcac aggtgacccc gatctggtgtccgagggccg 500 caaaagcttc cccagcatcc attcctcctt tgccttttcg ggccttggct550 tcacgacgtt ctacttggcg ggcaagctgc actgcttcac cgagagtggg 600cggggaaaga gctggcggct ctgtgctgcc atcctgccct tgtactgcgc 650 catgatgattgccctgtccc gcatgtgcga ctacaagcat cactggcaag 700 attcctttgt gggtggagtcatcgcgctca tttttgcata catttgctac 750 agacagcact atcctcctct gggccaacacagcttgccat aaaccctacg 800 ttagtctgcg agtttgccat aaaccctacg ttagtctgcgagtcccagcc 850 tcactgaaga aagaggagag gcccacagct gacagcgcac ccagcttgcc900 tctggagggg atcaccgaag gcccggtatg accagtgtcc tgggaggatg 950gacactaagc cctgggcaca tctgccaccc tgacatcata acacaataga 1000 aatggttttctgtagtgtat ttttcatcag ttgtttctca aagtcatcgt 1050 acttctgctt ctgtttcactgatggtgttc ctgctacttt aaatgtctac 1100 ttccaacatc cttgaatttg caagtgaaggacaacaatct ctgagagacg 1150 tgtggaagag gctgcgaagg tggggtttgg ggagcttcgccgattcgtct 1200 atctgaaatg tttgctgtaa cagccacctt cctatgtttt catggttagt1250 aaacataata aaacctccca tcgggaaaaa atacaaaatt cattgattta 1300ggaatatata tataatattc acatgtgtaa ttccccccct ccctttagtg 1350 agggtaattcaagatccttc tcaactgctt tgtgcgactt agactttatg 1400 ttgcagcaga cttttttattttacttatag cgcggaatcc gtgtttcctc 1450 agaatcaggg aatccgcccg aaaatctgttacaaaggccg ccaagtgaca 1500 taact 1505 44 1850 DNA Homo Sapien 44tccttgggtt cgggtgaaag cgcctggggg ttcgtggcca tgatccccga 50 gctgctggagaactgaaggc ggacagtctc ctgcgaaacc aggcaatggc 100 ggagctggag tttgttcagatcatcatcat cgtggtggtg atgatggtga 150 tggtggtggt gatcacgtgc ctgctgagccactacaagct gtctgcacgg 200 tccttcatca gccggcacag ccaggggcgg aggagagaagatgccctgtc 250 ctcagaagga tgcctgtggc cctcggagag cacagtgtca ggcaacggaa300 tcccagagcc gcaggtctac gccccgcctc ggcccaccga ccgcctggcc 350gtgccgccct tcgcccagcg ggagcgcttc caccgcttcc agcccaccta 400 tccgtacctgcagcacgaga tcgacctgcc acccaccatc tcgctgtcag 450 acggggagga gcccccaccctaccagggcc cctgcaccct ccagcttcgg 500 gaccccgagc agcagctgga actgaaccgggagtcggtgc gcgcaccccc 550 aaacagaacc atcttcgaca gtgacctgat ggatagtgccaggctgggcg 600 gcccctgccc ccccagcagt aactcgggca tcagcgccac gtgctacggc650 agcggcgggc gcatggaggg gccgccgccc acctacagcg aggtcatcgg 700ccactacccg gggtcctcct tccagcacca gcagagcagt gggccgccct 750 ccttgctggaggggacccgg ctccaccaca cacacatcgc gcccctagag 800 agcgcagcca tctggagcaaagagaaggat aaacagaaag gacaccctct 850 ctagggtccc caggggggcc gggctggggctgcgtaggtg aaaaggcaga 900 acactccgcg cttcttagaa gaggagtgag aggaaggcggggggcgcagc 950 aacgcatcgt gtggccctcc cctcccacct ccctgtgtat aaatatttac1000 atgtgatgtc tggtctgaat gcacaagcta agagagcttg caaaaaaaaa 1050aagaaaaaag aaaaaaaaaa accacgtttc tttgttgagc tgtgtcttga 1100 aggcaaaagaaaaaaaattt ctacagtagt ctttcttgtt tctagttgag 1150 ctgcgtgcgt gaatgcttattttcttttgt ttatgataat ttcacttaac 1200 tttaaagaca tatttgcaca aaacctttgtttaaagatct gcaatattat 1250 atatataaat atatataaga taagagaaac tgtatgtgcgagggcaggag 1300 tatttttgta ttagaagagg cctattaaaa aaaaaagttg ttttctgaac1350 tagaagagga aaaaaatggc aatttttgag tgccaagtca gaaagtgtgt 1400attaccttgt aaagaaaaaa attacaaagc aggggtttag agttatttat 1450 ataaatgttgagattttgca ctatttttta atataaatat gtcagtgctt 1500 gcttgatgga aacttctcttgtgtctgttg agactttaag ggagaaatgt 1550 cggaatttca gagtcgcctg acggcagagggtgagccccc gtggagtctg 1600 cagagaggcc ttggccagga gcggcgggct ttcccgaggggccactgtcc 1650 ctgcagagtg gatgcttctg cctagtgaca ggttatcacc acgttatata1700 ttccctaccg aaggagacac cttttccccc ctgacccaga acagccttta 1750aatcacaagc aaaataggaa agttaaccac ggaggcaccg agttccaggt 1800 agtggttttgcctttcccaa aaatgaaaat aaactgttac cgaaggaatt 1850 45 806 DNA Homo Sapien45 gcccttcgga cagtctcctg cgaaaccagg caatggcgga gctggagttt 50 gttcagatcatcatcatcgt ggtggtgatg atggtgatgg tggtggtgat 100 cacgtgcctg ctgagccactacaagctgtc tgcacggtcc ttcatcagcc 150 ggcacagcca ggggcggagg agagaagatgccctgtcctc agaaggatgc 200 ctgtggccct cggagagcac agtgtcaggc aacggaatcccagagccgca 250 ggtctacgcc ccgcctcggc ccaccgaccg cctggccgtg ccgcccttcg300 cccagcggga gcgcttccac cgcttccagc ccacctatcc gtacctgcag 350cacgagatcg acctgccgcc caccatctcg ctgtcagacg gggaggagcc 400 cccaccctaccagggcccct gcaccctcca gcttcgggac cccgagcagc 450 agctggaact gaaccgggagtcggtgcgcg cacccccaaa cagaaccatc 500 ttcgacagtg acctgatgga tagtgccaggctgggcggcc cctgcccccc 550 cagcagtaac tcgggcatca gcgccacgtg ctacggcagcggcgggcgca 600 tggaggggcc gccgcccacc tacagcgagg tcatcggcca ctacccgggg650 tcctccttcc agcaccagca gagcagtggg ccgccctcct tgctggaggg 700gacccggctc caccacacac acatcgcgcc cctagagagc gcagccatct 750 ggagcaaagagaaggataaa cagaaaggac accctctcta gggtccccag 800 aagggc 806 46 1982 DNAHomo Sapien 46 ggcgagaggc gggctgaggc ggcccagcgg cggcaggtga ggcggaacca 50accctcctgg ccatgggagg ggccgtggtg gacgagggcc ccacaggcgt 100 caaggcccctgacggcggct ggggctgggc cgtgctcttc ggctgtttcg 150 tcatcactgg cttctcctacgccttcccca aggccgtcag tgtcttcttc 200 aaggagctca tacaggagtt tgggatcggctacagcgaca cagcctggat 250 ctcctccatc ctgctggcca tgctctacgg gacaggtccgctctgcagtg 300 tgtgcgtgaa ccgctttggc tgccggcccg tcatgcttgt ggggggtctc350 tttgcgtcgc tgggcatggt ggctgcgtcc ttttgccgga gcatcatcca 400ggtctacctc accactgggg tcatcacggg gttgggtttg gcactcaact 450 tccagccctcgctcatcatg ctgaaccgct acttcagcaa gcggcgcccc 500 atggccaacg ggctggcggcagcaggtagc cctgtcttcc tgtgtgccct 550 gagcccgctg gggcagctgc tgcaggaccgctacggctgg cggggcggct 600 tcctcatcct gggcggcctg ctgctcaact gctgcgtgtgtgccgcactc 650 atgaggcccc tggtggtcac ggcccagccg ggctcggggc cgccgcgacc700 ctcccggcgc ctgctagacc tgagcgtctt ccgggaccgc ggctttgtgc 750tttacgccgt ggccgcctcg gtcatggtgc tggggctctt cgtcccgccc 800 gtgttcgtggtgagctacgc caaggacctg ggcgtgcccg acaccaaggc 850 cgccttcctg ctcaccatcctgggcttcat tgacatcttc gcgcggccgg 900 ccgcgggctt cgtggcgggg cttgggaaggtgcggcccta ctccgtctac 950 ctcttcagct tctccatgtt cttcaacggc ctcgcggacctggcgggctc 1000 tacggcgggc gactacggcg gcctcgtggt cttctgcatc ttctttggca1050 tctcctacgg catggtgggg gccctgcagt tcgaggtgct catggccatc 1100gtgggcaccc acaagttctc cagtgccatt ggcctggtgc tgctgatgga 1150 ggcggtggccgtgctcgtcg ggcccccttc gggaggcaaa ctcctggatg 1200 cgacccacgt ctacatgtacgtgttcatcc tggcgggggc cgaggtgctc 1250 acctcctccc tgattttgct gctgggcaacttcttctgca ttaggaagaa 1300 gcccaaagag ccacagcctg aggtggcggc cgcggaggaggagaagctcc 1350 acaagcctcc tgcagactcg ggggtggact tgcgggaggt ggagcatttc1400 ctgaaggctg agcctgagaa aaacggggag gtggttcaca ccccggaaac 1450aagtgtctga gtggctgggc ggggccggca ggcacaggga ggaggtacag 1500 aagccggcaacgcttgctat ttattttaca aactggactg gctcaggcag 1550 ggccacggct gggctccagctgccggccca gcggatcgtc gcccgatcag 1600 tgttttgagg gggaaggtgg cggggtgggaaccgtgtcat tccagagtgg 1650 atctgcggtg aagccaagcc gcaaggttac aaggcatcctcaccaggggc 1700 cccgcctgct gctcccaggt ggcctgcggc cactgctatg ctcaaggacc1750 tggaaaccca tgcttcgaga caacgtgact ttaatgggag ggtgggtggg 1800ccgcagacag gctggcaggg caggtgctgc gtggggccct ctccagcccg 1850 tcctaccctgggctcacatg gggcctgtgc ccacccctct tgagtgtctt 1900 ggggacagct ctttccacccctggaagatg gaaataaacc tgcgtgtggg 1950 tggagtgttc tcgtgccgaa ttcaaaaagctt 1982 47 2171 DNA Homo Sapien 47 cccacgcgtc cgcccacgcg tccgccgggtcctgcgcgct ccggactgag 50 gtggcgtccc tgggccggac ggcggtgtcc cggcgtggcgggaagccggc 100 actggagcgg gagcgcactg ggcgcgggac cgggaggcgc agggaccgga150 cggctcccga gtcgcccacc tgacggtacc gagagggcgg cgcccctccg 200agcagagccg tcccggccac tcccctggga tctgacttgg ctcttgcggt 250 cgcgggcaccgtgaagccct ggggtgtgcg tggctcctcc tggtaggcgc 300 cctttcccgg cgtccggcttggggtggtgg tggcgttgac tccagccccg 350 cctctccctg gagaggaggg ctccactcgctccttcggcc tcctcccctg 400 gggccgcagc gactcgggcc ggcttcctgc ttccctgcctgccggcggtc 450 ccgctggcta gaagaagtct tcacttccca ggagagccaa agcgtgtctg500 gccctaggtg ggaaaagaac tggctgtgac ctttgccctg acctggaagg 550gcccagcctt gggctgaatg gcagcaccca cgcccgcccg tccggtgctg 600 acccacctgctggtggctct cttcggcatg ggctcctggg ctgcggtcaa 650 tgggatctgg gtggagctacctgtggtggt caaagagctt ccagagggtt 700 ggagcctccc ctcttacgtc tctgtgcttgtggctctggg gaacctgggt 750 ctgctggtgg tgaccctctg gaggaggctg gccccaggaaaggacgagca 800 ggtccccatc cgggtggtgc aggtgctggg catggtgggc acagccctgc850 tggcctctct gtggcaccat gtggccccag tggcaggaca gttgcattct 900gtggccttct tagcactggc ctttgtgctg gcactggcat gctgtgcctc 950 gaatgtcactttcctgccct tcttgagcca cctgccacct cgcttcttac 1000 ggtcattctt cctgggtcaaggcctgagtg ccctgctgcc ctgcgtgctg 1050 gccctagtgc agggtgtggg ccgcctcgagtgcccgccag cccccatcaa 1100 cggcacccct ggccccccgc tcgacttcct tgagcgttttcccgccagca 1150 ccttcttctg ggcactgact gcccttctgg tcgcttcagc tgctgccttc1200 cagggtcttc tgctgctgtt gccgccacca ccatctgtac ccacagggga 1250gttaggatca ggcctccagg tgggagcccc aggagcagag gaagaggtgg 1300 aagagtcctcaccactgcaa gagccaccaa gccaggcagc aggcaccacc 1350 cctggtccag accctaaggcctatcagctt ctatcagccc gcagtgcctg 1400 cctgctgggc ctgttggccg ccaccaacgcgctgaccaat ggcgtgctgc 1450 ctgccgtgca gagcttttcc tgcttaccct acgggcgtctggcctaccac 1500 ctggctgtgg tgctgggcag tgctgccaat cccctggcct gcttcctggc1550 catgggtgtg ctgtgcaggt ccttggcagg gctgggcggc ctctctctgc 1600tgggcgtgtt ctgtgggggc tacctgatgg cgctggcagt cctgagcccc 1650 tgcccgcccctggtgggcac ctcggcgggg gtggtcctcg tggtgctgtc 1700 gtgggtgctg tgtcttggcgtgttctccta cgtgaaggtg gcagccagct 1750 ccctgctgca tggcgggggc cggccggcattgctggcagc cggcgtggcc 1800 atccaggtgg gctctctgct cggcgctgtt gctatgttccccccgaccag 1850 catctatcac gtgttccaca gcagaaagga ctgtgcagac ccctgtgact1900 cctgagcctg ggcaggtggg gaccccgctc cccaacacct gtctttccct 1950caatgctgcc accatgcctg agtgcctgca gcccaggagg cccgcacacc 2000 ggtacactcgtggacaccta cacactccat aggagatcct ggctttccag 2050 ggtgggcaag ggcaaggagcaggcttggag ccagggacca gtgggggctg 2100 tagggtaagc ccctgagcct gggacctacatgtggtttgc gtaataaaac 2150 atttgtattt aaaaaaaaaa a 2171 48 1617 DNA HomoSapien 48 gccagcacag ctgccctctg gaccctgcgg accccagccg agccccttcc 50tgagttccac aggcgcagcc cccgggcggt cgggcggagg ggtccccggg 100 gcggtgccaggcgcaatcct ggagggcggc cgggaggagg aggtgcgcgc 150 ggccatgcac accgtggctacgtccggacc caacgcgtcc tggggggcac 200 cggccaacgc ctccggctgc ccgggctgtggcgccaacgc ctcggacggc 250 ccagtccctt cgccgcgggc cgtggacgcc tggctcgtgccgctcttctt 300 cgcggcgctg atgctgctgg gcctggtggg gaactcgctg gtcatctacg350 tcatctgccg ccacaagccg atgcggaccg tgaccaactt ctacatcgcc 400aacctggcgg ccacggacgt gaccttcctc ctgtgctgcg tccccttcac 450 ggccctgctgtacccgctgc ccggctgggt gctgggcgac ttcatgtgca 500 agttcgtcaa ctacatccagcaggtctcgg tgcaggccac gtgtgccact 550 ctgaccgcca tgagtgtgga ccgctggtacgtgacggtgt tcccgttgcg 600 cgccctgcac cgccgcacgc cccgcctggc gctggctgtcagcctcagca 650 tctgggtagg ctctgcggcg gtgtctgcgc cggtgctcgc cctgcaccgc700 ctgtcacccg ggccgcgcgc ctactgcagt gaggccttcc ccagccgcgc 750cctggagcgc gccttcgcac tgtacaacct gctggcgctg tacctgctgc 800 cgctgctcgccacctgcgcc tgctatgcgg ccatgctgcg ccacctgggc 850 cgggtcgccg tgcgccccgcgcccgccgat agcgccctgc aggggcaggt 900 gctggcagag cgcgcaggcg ccgtgcgggccaaggtctcg cggctggtgg 950 cggccgtggt cctgctcttc gccgcctgct ggggccccatccagctgttc 1000 ctggtgctgc aggcgctggg ccccgcgggc tcctggcacc cacgcagcta1050 cgccgcctac gcgcttaaga cctgggctca ctgcatgtcc tacagcaact 1100ccgcgctgaa cccgctgctc tacgccttcc tgggctcgca cttccgacag 1150 gccttccgccgcgtctgccc ctgcgcgccg cgccgccccc gccgcccccg 1200 ccggcccgga ccctcggaccccgcagcccc acacgcggag ctgcaccgcc 1250 tggggtccca cccggccccc gccagggcgcagaagccagg gagcagtggg 1300 ctggccgcgc gcgggctgtg cgtcctgggg gaggacaacgcccctctttg 1350 agcggacccg gtgggaatcc gagcggctcc ctcgggagcg gggactgctg1400 gaacagcggc tattcttctg ttattagtat tttttttact gtccaagatc 1450aactgtggaa atattttggt ctcttgtgac gttcggtgca gtttcgttgt 1500 gaagtttgctattgatattg aaattatgac ttctgtgttt cctgaaatta 1550 aacatgtgtc aacacaggactttttggatc attccagaaa gtgtcagacg 1600 tttaaaaaaa aaaaaaa 1617 49 3095DNA Homo Sapien 49 ggcgcggggc gccatggcac accgagcggc tccgtcttctgctcctcaga 50 gagcccggct ggcggcctgg gatgacaaga tgtctggact gcaatcctgc 100acagttttga gagggagatg acttgagtgg ttggctttta tctccacaac 150 aatgtccatgaacaattcca aacagctagt gtctcctgca gctgcgcttc 200 tttcaaacac aacctgccagacggaaaacc ggctttccgt atttttttca 250 gtaatcttca tgacagtggg aatcttgtcaaacagccttg ccatcgccat 300 tctcatgaag gcatatcaga gatttagaca gaagtccaaggcatcgtttc 350 tgcttttggc cagcggcctg gtaatcactg atttctttgg ccatctcatc400 aatggagcca tagcagtatt tgtatatgct tctgataaag aatggatccg 450ctttgaccaa tcaaatgtcc tttgcagtat ttttggtatc tgcatggtgt 500 tttctggtctgtgcccactt cttctaggca gtgtgatggc cattgagcgg 550 tgtattggag tcacaaaaccaatatttcat tctacgaaaa ttacatccaa 600 acatgtgaaa atgatgttaa gtggtgtgtgcttgtttgct gttttcatag 650 ctttgctgcc catccttgga catcgagact ataaaattcaggcgtcgagg 700 acctggtgtt tctacaacac agaagacatc aaagactggg aagatagatt750 ttatcttcta cttttttctt ttctggggct cttagccctt ggtgtttcat 800tgttgtgcaa tgcaatcaca ggaattacac ttttaagagt taaatttaaa 850 agtcagcagcacagacaagg cagatctcat catttggaaa tggtaatcca 900 gctcctggcg ataatgtgtgtctcctgtat ttgttggagc ccatttctgg 950 ttacaatggc caacattgga ataaatggaaatcattctct ggaaacctgt 1000 gaaacaacac tttttgctct ccgaatggca acatggaatcaaatcttaga 1050 tccttgggta tatattcttc tacgaaaggc tgtccttaag aatctctata1100 agcttgccag tcaatgctgt ggagtgcatg tcatcagctt acatatttgg 1150gagcttagtt ccattaaaaa ttccttaaag gttgctgcta tttctgagtc 1200 accagttgcagagaaatcag caagcaccta gcttaatagg acagtaaatc 1250 tgtgtggggc tagaacaaaaattaagacat gtttggcaat atttcagtta 1300 gttaaatacc tgtagcctaa ctggaaaattcaggcttcat catgtagttt 1350 gaagatacta ttgtcagatt caggttttga aatttgtcaaataaacagga 1400 taactgtaca ttttcaactt gtttttgcca atgggaggta gacacaataa1450 aataatgcca tgggagtcac actgaaagca attttgagct tatctgtctt 1500atttatgctt tgagtgaatc atctgttgag gtctaatgcc tctacttggc 1550 ctatttgccagagaacatct taatgcagcc tgcatagtga aatggttatt 1600 ttgagatcac cgctctgtagctaaccctta taaactaggc tcagtaaaat 1650 aaagcactct tattttttga tctggcctattttgcccctc attgtgtagc 1700 ctcaattaac acatgcatgg tcatgacacc cagaattcatgatggtttgt 1750 tataacaacc tctgcatatt ccaggtctgg cagacaggtt gcctgaccct1800 gcaatcctat ctagaatggg cccattcttg tcacatttga caaataggac 1850tgcctacatt tattattatg aaggtcgatt gttgttggaa gtgttttttc 1900 atgtcatagattagcaattt tcaaataatt attttttctc tgaaaatttt 1950 gtgtgtgatt gcacaataaataatttttag agaaacaaag gctctttctc 2000 agcacattga tgggcaacta gaattacagcagtttcaaac tctaccatgg 2050 ataatgcaaa caaaccgaag ctacatgcca atgataggtgcaaagaatat 2100 tggcaaaagg tgctttacct tgagccatta tttgtgtcag agaacaaaag2150 aaacagaatc aatatataaa ttcaaagact atctgcagct agtgtgtttc 2200ttctttacac acatatacac acagacatca gaaaattctg ttgagagcag 2250 gttcattaaatttgtaagat ggcatattct aaagcctgtg ctaccagtac 2300 taagagggga agactggcaatttgccaagc acttggggat tattataaca 2350 attaactagg agatcaagag ataataatctctccccaaat tttccaataa 2400 taattgagac tttttctttg cttgtttgtg taattcaaccaaaagaattt 2450 caatacccat tcaaattgtc ctaggtctat cagaaattag ggaaggtagt2500 cctgctttat aataggaaaa tgtatttctg tataagattt ctttgctttc 2550attaaaaatg ggattcattt aaaaattaat ctttccctgt taggctgatt 2600 tcagattctctaggaaatct ggtgaagtaa ccagaagact ttcagatggt 2650 ttatttgctt tcagcagagaatttatttca tacagttact taagagtgtt 2700 gatgtcttgt gaacagagat ataaggaaccattctccatc cttccttatc 2750 atgctgggta caatgcttct atgaatattt ccatgtattttgactgggga 2800 gaggcatgga gaagaaactc tcattcaggg gctccaggat ccttctcctt2850 gaggcttcta aataaatggc agaattcttg ctgtattgcc atgatgtcac 2900cctggccatg tgtactgact tgaggagatc ttgcaacatg gccatgtgca 2950 aggctttaaggagtgagaga gatgtgtaca tatcttagga gggttatcta 3000 tgttatctga gtatatgtttgggtaaccaa attggtctta aaaatgatgt 3050 taacccaaga agtagacatc aaaaattaaaaaaaaaaaaa aaaaa 3095 50 6476 DNA Homo Sapien 50 atgtcacgca tgagccggcatccagacaag gacctggccc agggtccctt 50 caacacctgc tgtggctgca ccttaatggctagtcctgct aatctccctc 100 cgaacactca agcagctgca gaaagggccc tttcccagagcaggtggaag 150 agggtgcaag tgcccgcccc ggcatccctg tcccctttcc cactggccat200 ggcttcagtt gccttctgga tcagcatcct gattggctgc gaggaacaga 250ctctctgcag aggctggcgt agcccagtcg gggatggctg tgctcatgtg 300 cctccccaggagcgagcgac cgcagaggca gaccctccag ggcggtgcag 350 cacctccacg gcgtcgtctaccatctgtgg cctgtggcat ttgtccccac 400 ggctgcagct cctcccacct ctgcattccaggcagggaga agagtcgggc 450 aaaactgaga aggtgcttct ctggggaaga gagggcctccatgtgtggaa 500 acccggagtc ctgcagcccg atgtccacgg cacctccaac ctggggaact550 gctccttcct gcacggcctg gttacggctc cctcttgtcc acggcgggcg 600ggcgccgagc tgctgaattc tttaggaagt cagtttgcca ttagcctttt 650 tgaagttcagagtggaactg agcccagcat tacaggtgtg gccacgtcag 700 ggcagtgcag ggctatgccactgaagcatt atctcctttt gctggtgggc 750 tgccaagcct ggggtgcagg gttggcctaccatggctgcc ctagcgagtg 800 tacctgctcc agggcctccc aggtggagtg caccggggcacgcattgtgg 850 cggtgcccac ccctctgccc tggaacgcca tgagcctgca gatcctcaac900 acgcacatca ctgaactcaa tgagtccccg ttcctcaata tttcagccct 950catcgccctg aggattgaga agaatgagct gtcgcgcatc acgcctgggg 1000 ccttccgaaacctgggctcg ctgcgctatc tcagcctcgc caacaacaag 1050 ctgcaggttc tgcccatcggcctcttccag ggcctggaca gccttgagtc 1100 tctccttctg tccagtaacc agctgttgcagatccagccg gcccacttct 1150 cccagtgcag caacctcaag gagctgcagt tgcacggcaaccacctggaa 1200 tacatccctg acggagcctt cgaccacctg gtaggactca cgaagctcaa1250 tctgggcaag aatagcctca cccacatctc acccagggtc ttccagcacc 1300tgggcaatct ccaggtcctc cggctgtatg agaacaggct cacggatatc 1350 cccatgggcacttttgatgg gcttgttaac ctgcaggaac tggctctaca 1400 gcagaaccag attggactgctctcccctgg tctcttccac aacaaccaca 1450 acctccagag actctacctg tccaacaaccacatctccca gctgccaccc 1500 agcatcttca tgcagctgcc ccagctcaac cgtcttactctctttgggaa 1550 ttccctgaag gagctctctc tggggatctt cgggcccatg cccaacctgc1600 gggagctttg gctctatgac aaccacatct cttctctacc cgacaatgtc 1650ttcagcaacc tccgccagtt gcaggtcctg attcttagcc gcaatcagat 1700 cagcttcatctccccgggtg ccttcaacgg gctaacggag cttcgggagc 1750 tgtccctcca caccaacgcactgcaggacc tggacgggaa tgtcttccgc 1800 atgttggcca acctgcagaa catctccctgcagaacaatc gcctcagaca 1850 gctcccaggg aatatcttcg ccaacgtcaa tggcctcatggccatccagc 1900 tgcagaacaa ccagctggag aacttgcccc tcggcatctt cgatcacctg1950 gggaaactgt gtgagctgcg gctgtatgac aatccctgga ggtgtgactc 2000agacatcctt ccgctccgca actggctcct gctcaaccag cctaggttag 2050 ggacggacactgtacctgtg tgtttcagcc cagccaatgt ccgaggccag 2100 tccctcatta tcatcaatgtcaacgttgct gttccaagcg tccatgtacc 2150 tgaggtgcct agttacccag aaacaccatggtacccagac acacccagtt 2200 accctgacac cacatccgtc tcttctacca ctgagctaaccagccctgtg 2250 gaagactaca ctgatctgac taccattcag gtcactgatg accgcagcgt2300 ttggggcatg acccatgccc atagcgggct ggccattgcc gccattgtaa 2350ttggcattgt cgccctggcc tgctccctgg ctgcctgcgt cggctgttgc 2400 tgctgcaagaagaggagcca agctgtcctg atgcagatga aggcacccaa 2450 tgagtgttaa agaggcaggctggagcaggg ctggggaatg atgggactgg 2500 aggacctggg aatttcatct ttctgcctccacccctgggt ccatggagct 2550 ttcccgtgat tgctctttct ggccctagat aaaggtgtgcctacctcttc 2600 ctgacttgcc tgattctccc gtagagaagc aggtcgtgcc ggaccttcct2650 acaatcagga agatagatcc aactggccat ggcaaaagcc ctggggattt 2700ccgattcata cccctgggct tccttcgaga gggctcttcc tccaaatcct 2750 ccccacctgtcctccaagaa cagccttccc tgcgcccagg ccccctccgg 2800 gcctctgtag actcagttagtccacagcct gctcacttcg tgggaatagt 2850 tctccgctga gatagcccct ctcgcctaagtattatgtaa gttgatttcc 2900 cttcttttgt ttctcttgtt tgtgctatgg cttgacccagcatgtcccct 2950 caaatgaaag ttctcccctt gattttctgc tcctgaaggc agggtgagtt3000 ctctcctcaa agaagacttc aaaccattta actggtttct taagagccgt 3050caatcagcct ggttttgggg atgctatgaa agagagaagg aaaatcatgc 3100 cgctcagttcctggagacag aagagccgtc atcagtgtct cacttgtgat 3150 ttttatctgg aaaaggaagaaacaccccag cacagcaagc tcagcctttt 3200 agagaaggat atttccaaac tgcaaactttgctttgaaaa gtttagccct 3250 ttaaggaatg aaatcatgta gaattttgga cttctaaaaacattaaaatc 3300 agcttattaa tacgggatag agaaagaaat ctggtgcctg ggggtccctg3350 tgttcacccc tagagtttgt tttaaaattt ttaattgaag catgtgaagt 3400gtacctgcag aaaagtggga acatgatagt gtatggcttg gtggattttc 3450 acaaactgaacatacctgtg taatcagcat ctagacccag acccagagcg 3500 tcacaaatat cccccatcctgggcttttcc cagaggagat gggggcttct 3550 gaagatggac ttacctggga cctgccccccatgagccagg acggtccccc 3600 cacagtcagc ctgtgcaaag gccccgtggc caggggtggaggagaatatg 3650 tgggtgtgga caggatggga gactgtggcc tgaacaggag attttattat3700 atctggagac cctgagagac cctgagacct ggggcaccct ggctggccag 3750gtcagaagca tcctgactgc agaggtccgt gcagccacac cctcttccct 3800 gccagcaagctgtctgcggc tcatcggagg cccctccgcc tggagccttc 3850 tatggacgtg atatgcctgtatctgttttt aattttcatt cttcacttag 3900 gggaagtgaa atcgctcaga gatgagatcctttaattgaa aacgaagtgt 3950 aacggaatct agtgtctttc taatgtggta aaattctccatcaacatcac 4000 agtcagctgg cagctgaact tcagaatctc acttacagca ggcgacacgg4050 gggtacaccg atgggtcaca ctgggtctgg gggctccctg gagctcctcc 4100tgcgtgtggt ctggttagga gttgagttgt ttgctccagg gttattctcc 4150 tcctcgagtcacagtcacac gaatacctgc cttctctggc tttcctgcta 4200 tacacatatt cacatggcgctcaagaagtt aggctcatgg caacgtgtgt 4250 ctttctctgg acaactggcc cagtttacagtgaaatggag aatttcaggt 4300 ctccacgtct gcccaggaaa gaacttcagc tgactccacggggatctgga 4350 aatccacgac caatcccgat cggctcttat tagctccccg ctccacaaga4400 cacctgtgct ttggaaatcc accaccaatc ccgatcggct cttattagct 4450ccccgctcca caagacacct gtgatctgga aatctaccac caatcccgat 4500 cggctcttattagctccccg ctccacaaga cacctgtgac atcctccagg 4550 gccacaggag cacgtgctgaccagttttcc cttccagttc ctgcacaaaa 4600 agtgtccaga gggctgtttg caaacactagtgcactttgt agcttttcac 4650 cctctgtccc agggaatcta ggagagatga ggcccgtcagagtcaagaga 4700 tgtcatcccc ccagggtctc caaggcattt ccacactatt ggtggcacct4750 ggaggacatg caccaaggct tgccagagcc aacaggaagt gagcccagag 4800catggcacat gagcatcacc cgctgatggt ggcctgctgt gcctggtgcc 4850 aacaggggcatcccggccca tacccctcca gacaggaagc atgggtttgc 4900 ccacagacct gtcgggtgctcctgtgagtg gcctccagat gtctttgtgc 4950 ataggcacaa gtgggccagg gctggagggaggtgggaaac ctcatcatcc 5000 ggtgggccct gccaatctta acccagaacc cttaggtattcctggcagta 5050 gccatgacat tggagcacct tcctctccag ccagaggctg acctgagggc5100 cactgtcctc agatgacacc acccaggagc accctaggtg aggggtgagg 5150gcccccttat gtgaacctct tgcctcttcc tttctcccat cagagtggtt 5200 ggatggagccattggcctcc ttttcttcag cgggcccttc aacctctctg 5250 caccatgttg tctggctgaggagctactag aaaagctgag tggagtctcc 5300 tttccaacag gatgatgcat ttgctcaattctcagggctg gaatgagccg 5350 gctggtcccc cagaaagctg gagtggggta cagagttcagttttcctctc 5400 tgtttacagc tccttgacag tcccacgccc atctggagtg ggagctggga5450 gtcagtgttg gagaagaaac aacaaaagcc aattagaacc actattttta 5500aaaagtgctt actgtgcaca gatactcttc aagcactgga cgtggattct 5550 ctctctagccctcagcaccc ctgcggtagg agtgccgcct ctacccactt 5600 gtgatggggt acagaggcacttgctcttct gcatggtgtt caataggctg 5650 ggagttttat ttatctcttc aaactttgtacaagagctca tggcttgtct 5700 tgggctttcg tcattaaacc aaaggaaatg gaagccattcccctgttgct 5750 ctccttagtc ttggtcatca gaacctcact tggtaccata tagatcaaaa5800 gctttgtaac cacaggaaaa aataaactct tccatccctt aaagaataga 5850atagtttgtc cctctcatgg gaattgggct gtatgtatat tgttcttcct 5900 ccttagaatttagagataca agagttctac ttagaacttt tcatggacac 5950 aatttccaca acctttcagatgctgatgta gagctattgg gaaagaactt 6000 ccaaactcag gaagtttgca gagagcagacagctagagat aactcgggac 6050 ccagagttgg tcgacagatg ttagatgtat cctagcttttagctataaac 6100 cactcaaaga ttcagccccc agatcccaca gtcagaactg aatctgcgtt6150 gttgggaagc cagcagtggc cttgggaagg aagccatggc tgtggttcag 6200agagggtggg ctggcaagcc acttccgggg aaaactcctt ccgccccagg 6250 tttcttcttctcttaaggag agattattct caccaacccg ctgccttcat 6300 gctgccttca aagctagatcatgtttgcct tgcttagaga attactgcaa 6350 atcagcccca gtgcttggcg atgcatttacagatttctag gccctcaggg 6400 ttttgtagag tgtgagccct ggtgggcagg gttggggggtctgtcttctg 6450 ctggatgctg cttgtaatcc atttgg 6476 51 11389 DNA Homosapien 51 atggcgccgc cgccgccgcc cgtgctgccc gtgctgctgc tcctggccgc 50cgccgccgcc ctgccggcga tggggctgcg agcggccgcc tgggagccgc 100 gcgtacccggcgggacccgc gccttcgccc tccggcccgg ctgtacctac 150 gcggtgggcg ccgcttgcacgccccgggcg ccgcgggagc tgctggacgt 200 gggccgcgat gggcggctgg caggacgtcggcgcgtctcg ggcgcggggc 250 gcccgctgcc gctgcaagtc cgcttggtgg cccgcagtgccccgacggcg 300 ctgagccgcc gcctgcgggc gcgcacgcac cttcccggct gcggagcccg350 tgcccggctc tgcggaaccg gtgcccggct ctgcggggcg ctctgcttcc 400ccgtccccgg cggctgcgcg gccgcgcagc attcggcgct cgcagctccg 450 accaccttacccgcctgccg ctgcccgccg cgccccaggc cccgctgtcc 500 cggccgtccc atctgcctgccgccgggcgg ctcggtccgc ctgcgtctgc 550 tgtgcgccct gcggcgcgcg gctggcgccgtccgggtggg actggcgctg 600 gaggccgcca ccgcggggac gccctccgcg tcgccatccccatcgccgcc 650 cctgccgccg aacttgcccg aagcccgggc ggggccggcg cgacgggccc700 ggcggggcac gagcggcaga gggagcctga agtttccgat gcccaactac 750caggtggcgt tgtttgagaa cgaaccggcg ggcaccctca tcctccagct 800 gcacgcgcactacaccatcg agggcgagga ggagcgcgtg agctattaca 850 tggaggggct gttcgacgagcgctcccggg gctacttccg aatcgactct 900 gccacgggcg ccgtgagcac ggacagcgtactggaccgcg agaccaagga 950 gacgcacgtc ctcagggtga aagccgtgga ctacagtacgccgccgcgct 1000 cggccaccac ctacatcact gtcttggtca aagacaccaa cgaccacagc1050 ccggtcttcg agcagtcgga gtaccgcgag cgcgtgcggg agaacctgga 1100ggtgggctac gaggtgctga ccatccgcgc cagcgaccgc gactcgccca 1150 tcaacgccaacttgcgttac cgcgtgttgg ggggcgcgtg ggacgtcttc 1200 cagctcaacg agagctctggcgtggtgagc acacgggcgg tgctggaccg 1250 ggaggaggcg gccgagtacc agctcctggtggaggccaac gaccaggggc 1300 gcaatccggg cccgctcagt gccacggcca ccgtgtacatcgaggtggag 1350 gacgagaacg acaactaccc ccagttcagc gagcagaact acgtggtcca1400 ggtgcccgag gacgtggggc tcaacacggc tgtgctgcga gtgcaggcca 1450cggaccggga ccagggccag aacgcggcca ttcactacag catcctcagc 1500 gggaacgtggccggccagtt ctacctgcac tcgctgagcg ggatcctgga 1550 tgtgatcaac cccttggatttcgaggatgt ccagaaatac tcgctgagca 1600 ttaaggccca ggatgggggc cggcccccgctcatcaattc ttcaggggtg 1650 gtgtctgtgc aggtgctgga tgtcaacgac aacgagcctatctttgtgag 1700 cagccccttc caggccacgg tgctggagaa tgtgcccctg ggctaccccg1750 tggtgcacat tcaggcggtg gacgcggact ctggagagaa cgcccggctg 1800cactatcgcc tggtggacac ggcctccacc tttctggggg gcggcagcgc 1850 tgggcctaagaatcctgccc ccacccctga cttccccttc cagatccaca 1900 acagctccgg ttggatcacagtgtgtgccg agctggaccg cgaggaggtg 1950 gagcactaca gcttcggggt ggaggcggtggaccacggct cgccccccat 2000 gagctcctcc accagcgtgt ccatcacggt gctggacgtgaatgacaacg 2050 acccggtgtt cacgcagccc acctacgagc ttcgtctgaa tgaggatgcg2100 gccgtgggga gcagcgtgct gaccctgcag gcccgcgacc gtgacgccaa 2150cagtgtgatt acctaccagc tcacaggcgg caacacccgg aaccgctttg 2200 cactcagcagccagagaggg ggcggcctca tcaccctggc gctacctctg 2250 gactacaagc aggagcagcagtacgtgctg gcggtgacag catccgacgg 2300 cacacggtcg cacactgcgc atgtcctaatcaacgtcact gatgccaaca 2350 cccacaggcc tgtctttcag agctcccatt acacagtgagtgtcagtgag 2400 gacaggcctg tgggcacctc cattgctacc ctcagtgcca acgatgagga2450 cacaggagag aatgcccgca tcacctacgt gattcaggac cccgtgccgc 2500agttccgcat tgaccccgac agtggcacca tgtacaccat gatggagctg 2550 gactatgagaaccaggtcgc ctacacgctg accatcatgg cccaggacaa 2600 cggcatcccg cagaaatcagacaccaccac cctagagatc ctcatcctcg 2650 atgccaatga caatgcaccc cagttcctgtgggatttcta ccagggttcc 2700 atctttgagg atgctccacc ctcgaccagc atcctccaggtctctgccac 2750 ggaccgggac tcaggtccca atgggcgtct gctgtacacc ttccagggtg2800 gggacgacgg cgatggggac ttctacatcg agcccacgtc cggtgtgatt 2850cgcacccagc gccggctgga ccgggagaat gtggccgtgt acaacctttg 2900 ggctctggctgtggatcggg gcagtcccac tccccttagc gcctcggtag 2950 aaatccaggt gaccatcttggacattaatg acaatgcccc catgtttgag 3000 aaggacgaac tggagctgtt tgttgaggagaacaacccag tggggtcggt 3050 ggtggcaaag attcgtgcta acgaccctga tgaaggccctaatgcccaga 3100 tcatgtatca gattgtggaa ggggacatgc ggcatttctt ccagctggac3150 ctgctcaacg gggacctgcg tgccatggtg gagctggact ttgaggtccg 3200gcgggagtat gtgctggtgg tgcaggccac gtcggctccg ctggtgagcc 3250 gagccacggtgcacatcctt ctcgtggacc agaatgacaa cccgcctgtg 3300 ctgcccgact tccagatcctcttcaacaac tatgtcacca acaagtccaa 3350 cagtttcccc accggcgtga tcggctgcatcccggcccat gaccccgacg 3400 tgtcagacag cctcaactac accttcgtgc agggcaacgagctgcgcctg 3450 ttgctgctgg accccgccac gggcgaactg cagctcagcc gcgacctgga3500 caacaaccgg ccgctggagg cgctcatgga ggtgtctgtg tctgatggca 3550tccacagcgt cacggccttc tgcaccctgc gtgtcaccat catcacggac 3600 gacatgctgaccaacagcat cactgtccgc ctggagaaca tgtcccagga 3650 gaagttcctg tccccgctgctggccctctt cgtggagggg gtggccgccg 3700 tgctgtccac caccaaggac gacgtcttcgtcttcaacgt ccagaacgac 3750 accgacgtca gctccaacat cctgaacgtg accttctcggcgctgctgcc 3800 tggcggcgtc cgcggccagt tcttcccgtc ggaggacctg caggagcaga3850 tctacctgaa tcggacgctg ctgaccacca tctccacgca gcgcgtgctg 3900cccttcgacg acaacatctg cctgcgcgag ccctgcgaga actacatgaa 3950 gtgcgtgtccgttctgcgat tcgacagctc cgcgcccttc ctcagctcca 4000 ccaccgtgct cttccggcccatccacccca tcaacggcct gcgctgccgc 4050 tgcccgcccg gcttcaccgg cgactactgcgagacggaga tcgacctctg 4100 ctactccgac ccgtgcggcg ccaacggccg ctgccgcagccgcgagggcg 4150 gctacacctg cgagtgcttc gaggacttca ctggagagca ctgtgaggtg4200 gatgcccgct caggccgctg tgccaacggg gtgtgcaaga acgggggcac 4250ctgcgtgaac ctgctcatcg gcggcttcca ctgcgtgtgt cctcctggcg 4300 agtatgagaggccctactgt gaggtgacca ccaggagctt cccgccccag 4350 tccttcgtca ccttccggggcctgagacag cgcttccact tcaccatctc 4400 cctcacgttt gccactcagg aaaggaacggcttgcttctc tacaacggcc 4450 gcttcaatga gaagcacgac ttcatcgccc tggagatcgtggacgagcag 4500 gtgcagctca ccttctctgc aggcgagaca acaacgaccg tggcaccgaa4550 ggttcccagt ggtgtgagtg acgggcggtg gcactctgtg caggtgcagt 4600actacaacaa gcccaatatt ggccacctgg gcctgcccca tgggccgtcc 4650 ggggaaaagatggccgtggt gacagtggat gattgtgaca caaccatggc 4700 tgtgcgcttt ggaaaggacatcgggaacta cagctgcgct gcccagggca 4750 ctcagaccgg ctccaagaag tccctggatctgaccggccc tctactcctg 4800 gggggtgtcc ccaacctgcc agaagacttc ccagtgcacaaccggcagtt 4850 cgtgggctgc atgcggaacc tgtcagtcga cggcaaaaat gtggacatgg4900 ccggattcat cgccaacaat ggcacccggg aaggctgcgc tgctcggagg 4950aacttctgcg atgggaggcg gtgtcagaat ggaggcacct gtgtcaacag 5000 gtggaatatgtatctgtgtg agtgtccact ccgattcggc gggaagaact 5050 gtgagcaagc catgcctcacccccagctct tcagcggtga gagcgtcgtg 5100 tcctggagtg acctgaacat catcatctctgtgccctggt acctggggct 5150 catgttccgg acccggaagg aggacagcgt tctgatggaggccaccagtg 5200 gtgggcccac cagctttcgc ctccagatcc tgaacaacta cctccagttt5250 gaggtgtccc acggcccctc cgatgtggag tccgtgatgc tgtccgggtt 5300gcgggtgacc gacggggagt ggcaccacct gctgatcgag ctgaagaatg 5350 ttaaggaggacagtgagatg aagcacctgg tcaccatgac cttggactat 5400 gggatggacc agaacaaggcagatatcggg ggcatgcttc ccgggctgac 5450 ggtaaggagc gtggtggtcg gaggcgcctctgaagacaag gtctccgtgc 5500 gccgtggatt ccgaggctgc atgcagggag tgaggatgggggggacgccc 5550 accaacgtcg ccaccctgaa catgaacaac gcactcaagg tcagggtgaa5600 ggacggctgt gatgtggacg acccctgtac ctcgagcccc tgtcccccca 5650atagccgctg ccacgacgcc tgggaggact acagctgcgt ctgtgacaaa 5700 gggtaccttggaataaactg tgtggatgcc tgtcacctga acccctgcga 5750 gaacatgggg gcctgcgtgcgctcccccgg ctccccgcag ggctacgtgt 5800 gcgagtgtgg gcccagtcac tacgggccgtactgtgagaa caaactcgac 5850 cttccgtgcc ccagaggctg gtgggggaac cccgtctgtggaccctgcca 5900 ctgtgccgtc agcaaaggct ttgatcccga ctgtaataag accaacggcc5950 agtgccaatg caaggagaat tactacaagc tcctagccca ggacacctgt 6000ctgccctgcg actgcttccc ccatggctcc cacagccgca cttgcgacat 6050 ggccaccgggcagtgtgcct gcaagcccgg cgtcatcggc cgccagtgca 6100 accgctgcga caacccgtttgccgaggtca ccacgctcgg ctgtgaagtg 6150 atctacaatg gctgtcccaa agcatttgaggccggcatct ggtggccaca 6200 gaccaagttc gggcagccgg ctgcggtgcc atgccctaagggatccgttg 6250 gaaatgcggt ccgacactgc agcggggaga agggctggct gcccccagag6300 ctctttaact gtaccaccat ctccttcgtg gacctcaggg ccatgaatga 6350gaagctgagc cgcaatgaga cgcaggtgga cggcgccagg gccctgcagc 6400 tggtgagggcgctgcgcagt gctacacagc acacgggcac gctctttggc 6450 aatgacgtgc gcacggcctaccagctgctg ggccacgtcc ttcagcacga 6500 gagctggcag cagggcttcg acctggcagccacgcaggac gccgactttc 6550 acgaggacgt catccactcg ggcagcgccc tcctggccccagccaccagg 6600 gcggcgtggg agcagatcca gcggagcgag ggcggcacgg cacagctgct6650 ccggcgcctc gagggctact tcagcaacgt ggcacgcaac gtgcggcgga 6700cgtacctgcg gcccttcgtc atcgtcaccg ccaacatgat tcttgctgtc 6750 gacatctttgacaagttcaa ctttacggga gccagggtcc cgcgattcga 6800 caccatccat gaagagttccccagggagct ggagtcctcc gtctccttcc 6850 cagccgactt cttcagacca cctgaagaaaaagaaggccc cctgctgagg 6900 ccggctggcc ggaggaccac cccgcagacc acgcgcccggggcctggcac 6950 cgagagggag gccccgatca gcaggcggag gcgacaccct gatgacgctg7000 gccagttcgc cgtcgctctg gtcatcattt accgcaccct ggggcagctc 7050ctgcccgagc gctacgaccc cgaccgtcgc agcctccggt tgcctcaccg 7100 gcccatcattaataccccga tggtgagcac gctggtgtac agcgaggggg 7150 ctccgctccc gagacccctggagaggcccg tcctggtgga gttcgccctg 7200 ctggaggtgg aggagcgaac caagcctgtctgcgtgttct ggaaccactc 7250 cctggccgtt ggtgggacgg gagggtggtc tgcccggggctgcgagctcc 7300 tgtccaggaa ccggacacat gtcgcctgcc agtgcagcca cacagccagc7350 tttgcggtgc tcatggatat ctccaggcgt gagaacgggg aggtcctgcc 7400tctgaagatt gtcacctatg ccgctgtgtc cttgtcactg gcagccctgc 7450 tggtggccttcgtcctcctg agcctggtcc gcatgctgcg ctccaacctg 7500 cacagcattc acaagcacctcgccgtggcg ctcttcctct ctcagctggt 7550 gttcgtgatt gggatcaacc agacggaaaacccgtttctg tgcacagtgg 7600 ttgccatcct cctccactac atctacatga gcacctttgcctggaccctc 7650 gtggagagcc tgcatgtcta ccgcatgctg accgaggtgc gcaacatcga7700 cacggggccc atgcggttct actacgtcgt gggctggggc atcccggcca 7750ttgtcacagg actggcggtc ggcctggacc cccagggcta cgggaacccc 7800 gacttctgctggctgtcgct tcaagacacc ctgatttgga gctttgcggg 7850 gcccatcgga gctgttataatcatcaacac agtcacttct gtcctatctg 7900 caaaggtttc ctgccaaaga aagcaccattattatgggaa aaaagggatc 7950 gtctccctgc tgaggaccgc attcctcctg ctgctgctcatcagcgccac 8000 ctggctgctg gggctgctgg ctgtgaaccg cgatgcactg agctttcact8050 acctcttcgc catcttcagc ggcttacagg gccccttcgt cctccttttc 8100cactgcgtgc tcaaccagga ggtccggaag cacctgaagg gcgtgctcgg 8150 cgggaggaagctgcacctgg aggactccgc caccaccagg gccaccctgc 8200 tgacgcgctc cctcaactgcaacaccacct tcggtgacgg gcctgacatg 8250 ctgcgcacag acttgggcga gtccaccgcctcgctggaca gcatcgtcag 8300 ggatgaaggg atccagaagc tcggcgtgtc ctctgggctggtgaggggca 8350 gccacggaga gccagacgcg tccctcatgc ccaggagctg caaggatccc8400 cctggccacg attccgactc agatagcgag ctgtccctgg atgagcagag 8450cagctcttac gcctcctcac actcgtcaga cagcgaggac gatggggtgg 8500 gagctgaggaaaaatgggac ccggccaggg gcgccgtcca cagcaccccc 8550 aaaggggacg ctgtggccaaccacgttccg gccggctggc ccgaccagag 8600 cctggctgag agtgacagtg aggaccccagcggcaagccc cgcctgaagg 8650 tggagaccaa ggtcagcgtg gagctgcacc gcgaggagcagggcagtcac 8700 cgtggagagt accccccgga ccaggagagc gggggcgcag ccaggcttgc8750 tagcagccag cccccagagc agaggaaagg catcttgaaa aataaagtca 8800cctacccgcc gccgctgacg ctgacggagc agacgctgaa gggccggctc 8850 cgggagaagctggccgactg tgagcagagc cccacatcct cgcgcacgtc 8900 ttccctgggc tctggcggccccgactgcgc catcacagtc aagagccctg 8950 ggagggagcc ggggcgtgac cacctcaacggggtggccat gaatgtgcgc 9000 actgggagcg cccaggccga tggctccgac tctgagaaaccgtgaggcaa 9050 gcccgtcacc ccacacaggc tgcggcatca ccctcagacc ttggagccca9100 aggggccact gcccttgaag tggagtgggc ccagagtgtg gcggtcccca 9150tggtggcagc cccccgactg atcatccaga cacaaaggtc ttggttctcc 9200 caggagctcagggcctgtca gacctggtga caagtgccaa aggccacagg 9250 catgagggag gcgtggaccactgggccagc accgctgagt cctaagactg 9300 cagtcaaagc cagaactgag aggggaccccagactgggcc cagaggctgg 9350 ccagagttca ggaacgccgg gcacagacca aagaccgcggtccagccccg 9400 cccaggcggg catctcatgg cagtgcggac ccgtggctgg cagcccgggc9450 agtcctttgc aaaggcaccc cttgtcttaa aatcacttcg ctatgtggga 9500aaggtggaga tacttttata tatttgtatg ggactctgag gaggtgcaac 9550 ctgtatatatattgcattcg tgctgacttt gttatcccga gagatccatg 9600 caatgatctc ttgctgtcttctctgtcaag attgcacagt tgtacttgaa 9650 tctggcatgt gttgacgaaa ctggtgccccagcagatcaa aggtgggaaa 9700 tacgtcagca gtggggctaa aaccaagcgg ctagaagccctacagctgcc 9750 ttcggccagg aagtgaggat ggtgtgggcc ctccccgccg gccccctggg9800 tccccagtgt tcgctgtgtg tgcgtttgtc ctctgctgcc atctgccccg 9850gctgtgtgaa ttcaagacag ggcagtgcag cactaggcag gtgtgaggag 9900 ccctgctgaggtcactgtgg ggcacggttg ccacacggct gtcatttttc 9950 acctggtcat tctgtgaccaccaccccctc ccctcaccgc ctcccaggtg 10000 gcccgggagc tgcaggtggg gatggctttgtcctttgctc ctgctccccg 10050 tgggacctgg gaccttaaag cgttgcaggt tcctgatttggacagaggtg 10100 tggggccttc caggccgtta catacctcct gccaattctc taactctctg10150 agactgcgag gatctccagg cagggttctc ccctctggag tctgaccaat 10200tacttcattt tgcttcaaat ggccaattgt gcagagggac aaagccacag 10250 ccacactcttcaacggttac caaactgttt ttggaaattc acaccaaggt 10300 cgggcccact gcaggcagctggcacagcgt ggcccgaggg gctgtggaac 10350 gggtcccgga actgtcagac atgtttgattttagcgtttc ctttgttctt 10400 caaatcaggt gcccaaataa gtgatcagca cagctgcttccaaataggag 10450 aaaccataaa ataggatgaa aatcaagtaa aatgcaaaga tgtccacact10500 gttttaaact tgaccctgat gaaaatgtga gcactgttag cagatgccta 10550tgggagagga aaagcgtatc tgaaaatggt ccaggacagg aggatgaaat 10600 gagatcccagagtcctcaca cctgaatgaa ttatacatgt gccttaccag 10650 gtgagtggtc tttcgaagataaaaaactct agtcccttta aacgtttgcc 10700 cctggcgttt cctaagtacg aaaaggtttttaagtcttcg aacagtctcc 10750 tttcatgact ttaacaggat tctgccccct gaggtgtaatttttttgttc 10800 tatttttttc cacgtactcc acagccaaca tcacgaggtg taatttttaa10850 tttgatcaga actgttacca aaaaacaact gtcagtttta ttgagatggg 10900aaaaatgtaa acctattttt attacttaag actttatggg agagattaga 10950 cactggaggtttttaacaga acgtgtattt attaatgttc aaaacactgg 11000 aattacaaat gagaagagtctacaataaat taagattttt gaatttgtac 11050 ttctgcggtg ctggtttttc tccacaaacacccccgcccc tccccatgcc 11100 cagggtggcc gtggaaggga cggtttacgg acgtgcagctgagctgtccg 11150 tgtcccatgc tccctcagcc agtggaacgt gccggaactt tttgtccatt11200 ccctagtagg cctgccacag cctagatggg cagtttttgt ctttcaccaa 11250atttgaggac tttttttttt tgccattatt tcttcagttt tcttttcttg 11300 cactgatctttctcctctcc ttctgtgact ccagtgactc agacgttaga 11350 cctcttgatg ttttcccactggtccctgag gctctgttc 11389 52 1107 DNA Homo Sapien unsure 170-208unknown base 52 cggcctaagg tagcgacggg actggccggg ggcggcagga cccgaaggcg50 ctaggcggat tcaccggatg ggagttgaat cgcgtcccgg tctttctagc 100 tgtgcccggaaatcgggcgt gcgggcagct acagcagaga atcggacaag 150 gagggaagaa agagatggtnnnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 200 nnnnnnnnga agtgagtgca agaggagccggcttagcatc taaactgatt 250 ctaccatcag aaaagaggcc aaacttctat catcatggtggatgtgaagt 300 gtctgagtga ctgtaaattg cagaaccaac ttgagaagct tggattttca350 cctggcccaa tactaccttc caccagaaag ttgtatgaaa aaaagttagt 400acagttgttg gtctcacctc cctgtgcacc acctgtgatg aatggaccca 450 gagagctggatggagcgcag gacagtgatg acagcgaaga gcttaatatc 500 attttgcaag gaaatatcatactctcaaca gaaaaaagca agaaactcaa 550 aaaatggcct gaggcttcca ccactaaacgcaaagctgta gatacctatt 600 gcttggatta taagccttcc aagggaagaa ggtgggctgcaagagcacca 650 agcaccagaa tcacatatgg gactatcacc aaagagagag actactgcgc700 ggaagaccag actatcgaga gctggagaga agaaggtttc ccagtgggct 750tgaagcttgc tgtgcttggt attttcatca ttgtggtgtt tgtctacctg 800 actgtggaaaataagtcgct gtttggttaa gtaatttagg agcaaagcaa 850 tgctccaagc gaggcctcctgcttcaggaa agaaccaaaa cactaccctg 900 aagggccagc ctagcctgca gccctcccttgcagggagcc ttcccttgca 950 ctgtgctgct ctcacagatc ggtgtctggg ctcagccaggtggaaggaac 1000 ctgcctaacc aggcacctgt gttaagagca tgatggttag gaaatccccc1050 aagtcatgtc aactctcatt aaaggtgctt ccatatttga gcaggcgtca 1100 aacaagg1107 53 3946 DNA Homo Sapien 53 accgctccgg agcgggaggg gaggcttcgcggaacgctct cggcgccagg 50 actcgcgtgc aaagcccagg cccgggcggc cagaccaagagggaagaagc 100 acagaattcc tcaactccca gtgtgcccat gagtaagagc aaatgctccg150 tgggactcat gtcttccgtg gtggccccgg ctaaggagcc caatgccgtg 200ggcccgaagg aggtggagct catccttgtc aaggagcaga acggagtgca 250 gctcaccagctccaccctca ccaacccgcg gcagagcccc gtggaggccc 300 aggatcggga gacctggggcaagaagatcg actttctcct gtccgtcatt 350 ggctttgctg tggacctggc caacgtctggcggttcccct acctgtgcta 400 caaaaatggt ggcggtgcct tcctggtccc ctacctgctcttcatggtca 450 ttgctgggat gccacttttc tacatggagc tggccctcgg ccagttcaac500 agggaagggg ccgctggtgt ctggaagatc tgccccatac tgaaaggtgt 550gggcttcacg gtcatcctca tctcactgta tgtcggcttc ttctacaacg 600 tcatcatcgcctgggcgctg cactatctct tctcctcctt caccacggag 650 ctcccctgga tccactgcaacaactcctgg aacagcccca actgctcgga 700 tgcccatcct ggtgactcca gtggagacagctcgggcctc aacgacactt 750 ttgggaccac acctgctgcc gagtactttg aacgtggcgtgctgcacctc 800 caccagagcc atggcatcga cgacctgggg cctccgcggt ggcagctcac850 agcctgcctg gtgctggtca tcgtgctgct ctacttcagc ctctggaagg 900gcgtgaagac ctcagggaag gtggtatgga tcacagccac catgccatac 950 gtggtcctcactgccctgct cctgcgtggg gtcaccctcc ctggagccat 1000 agacggcatc agagcatacctgagcgttga cttctaccgg ctctgcgagg 1050 cgtctgtttg gattgacgcg gccacccaggtgtgcttctc cctgggcgtg 1100 gggttcgggg tgctgatcgc cttctccagc tacaacaagttcaccaacaa 1150 ctgctacagg gacgcgattg tcaccacctc catcaactcc ctgacgagct1200 tctcctccgg cttcgtcgtc ttctccttcc tggggtacat ggcacagaag 1250cacagtgtgc ccatcgggga cgtggccaag gacgggccag ggctgatctt 1300 catcatctacccggaagcca tcgccacgct ccctctgtcc tcagcctggg 1350 ccgtggtctt cttcatcatgctgctcaccc tgggtatcga cagcgccatg 1400 ggtggtatgg agtcagtgat caccgggctcatcgatgagt tccagctgct 1450 gcacagacac cgtgagctct tcacgctctt catcgtcctggcgaccttcc 1500 tcctgtccct gttctgcgtc accaacggtg gcatctacgt cttcacgctc1550 ctggaccatt ttgcagccgg cacgtccatc ctctttggag tgctcatcga 1600agccatcgga gtggcctggt tctatggtgt tgggcagttc agcgacgaca 1650 tccagcagatgaccgggcag cggcccagcc tgtactggcg gctgtgctgg 1700 aagctggtca gcccctgctttctcctgttc gtggtcgtgg tcagcattgt 1750 gaccttcaga cccccccact acggagcctacatcttcccc gactgggcca 1800 acgcgctggg ctgggtcatc gccacatcct ccatggccatggtgcccatc 1850 tatgcggcct acaagttctg cagcctgcct gggtcctttc gagagaaact1900 ggcctacgcc attgcacccg agaaggaccg tgagctggtg gacagagggg 1950aggtgcgcca gttcacgctc cgccactggc tcaaggtgta gagggagcag 2000 agacgaagaccccaggaagt catcctgcaa tgggagagac acgaacaaac 2050 caaggaaatc taagtttcgagagaaaggag ggcaacttct actcttcaac 2100 ctctactgaa aacacaaaca acaaagcagaagactcctct cttctgactg 2150 tttacacctt tccgtgccgg gagcgcacct cgccgtgtcttgtgttgctg 2200 taataacgac gtagatctgt gcagcgaggt ccaccccgtt gttgtccctg2250 cagggcagaa aaacgtctaa cttcatgctg tctgtgtgag gctccctccc 2300tccctgctcc ctgctcccgg ctctgaggct gccccagggg cactgtgttc 2350 tcaggcggggatcacgatcc ttgtagacgc acctgctgag aatccccgtg 2400 ctcacagtag cttcctagaccatttacttt gcccatatta aaaagccaag 2450 tgtcctgctt ggtttagctg tgcagaaggtgaaatggagg aaaccacaaa 2500 ttcatgcaaa gtcctttccc gatgcgtggc tcccagcagaggccgtaaat 2550 tgagcgttca gttgacacat tgcacacaca gtctgttcag aggcattgga2600 ggatgggggt cctggtatgt ctcaccagga aattctgttt atgttcttgc 2650agcagagaga aataaaactc cttgaaacca gctcaggcta ctgccactca 2700 ggcagcctgtgggtccttgt ggtgtaggga acggcctgag aggagcgtgt 2750 cctatccccg gacgcatgcagggcccccac aggagcgtgt cctatccccg 2800 gacgcatgca gggcccccac aggagcatgtcctatccctg gacgcatgca 2850 gggcccccac aggagcgtgt actaccccag aacgcatgcagggcccccac 2900 aggagcgtgt actaccccag gacgcatgca gggcccccac tggagcgtgt2950 actaccccag gacgcatgca gggcccccac aggagcgtgt cctatccccg 3000gaccggacgc atgcagggcc cccacaggag cgtgtactac cccaggacgc 3050 atgcagggcccccacaggag cgtgtactac cccaggatgc atgcagggcc 3100 cccacaggag cgtgtactaccccaggacgc atgcagggcc cccatgcagg 3150 cagcctgcag accaacactc tgcctggccttgagccgtga cctccaggaa 3200 gggaccccac tggaatttta tttctctcag gtgcgtgccacatcaataac 3250 aacagttttt atgtttgcga atggcttttt aaaatcatat ttacctgtga3300 atcaaaacaa attcaagaat gcagtatccg cgagcctgct tgctgatatt 3350gcagtttttg tttacaagaa taattagcaa tactgagtga aggatgttgg 3400 ccaaaagctgctttccatgg cacactgccc tctgccactg acaggaaagt 3450 ggatgccata gtttgaattcatgcctcaag tcggtgggcc tgcctacgtg 3500 ctgcccgagg gcaggggccg tgcagggccagtcatggctg tcccctgcaa 3550 gtggacgtgg gctccaggga ctggagtgta atgctcggtgggagccgtca 3600 gcctgtgaac tgccaggcag ctgcagttag cacagaggat ggcttcccca3650 ttgccttctg gggagggaca cagaggacgg cttccccatc gccttctggc 3700cgctgcagtc agcacagaga gcggcttccc cattgccttc tggggaggga 3750 cacagaggacagtttcccca tcgccttctg gttgttgaag acagcacaga 3800 gagcggcttc cccatcgccttctggggagg ggctccgtgt agcaacccag 3850 gtgttgtccg tgtctgttga ccaatctctattcagcatcg tgtgggtccc 3900 taagcacaat aaaagacatc cacaatggaa aaaaaaaaaggaattc 3946 54 2317 DNA Homo Sapien 54 cggacgcgtg ggtgagcagg gacggtgcaccggacggcgg gatcgagcaa 50 atgggtctgg ccatggagca cggagggtcc tacgctcgggcggggggcag 100 ctctcggggc tgctggtatt acctgcgcta cttcttcctc ttcgtctccc150 tcatccaatt cctcatcatc ctggggctcg tgctcttcat ggtctatggc 200aacgtgcacg tgagcacaga gtccaacctg caggccaccg agcgccgagc 250 cgagggcctatacagtcagc tcctagggct cacggcctcc cagtccaact 300 tgaccaagga gctcaacttcaccacccgcg ccaaggatgc catcatgcag 350 atgtggctga atgctcgccg cgacctggaccgcatcaatg ccagcttccg 400 ccagtgccag ggtgaccggg tcatctacac gaacaatcagaggtacatgg 450 ctgccatcat cttgagtgag aagcaatgca gagatcaatt caaggacatg500 aacaagagct gcgatgcctt gctcttcatg ctgaatcaga aggtgaagac 550gctggaggtg gagatagcca aggagaagac catttgcact aaggataagg 600 aaagcgtgctgctgaacaaa cgcgtggcgg aggaacagct ggttgaatgc 650 gtgaaaaccc gggagctgcagcaccaagag cgccagctgg ccaaggagca 700 actgcaaaag gtgcaagccc tctgcctgcccctggacaag gacaagtttg 750 agatggacct tcgtaacctg tggagggact ccattatcccacgcagcctg 800 gacaacctgg gttacaacct ctaccatccc ctgggctcgg aattggcctc850 catccgcaga gcctgcgacc acatgcccag cctcatgagc tccaaggtgg 900aggagctggc ccggagcctc cgggcggata tcgaacgcgt ggcccgcgag 950 aactcagacctccaacgcca gaagctggaa gcccagcagg gcctgcgggc 1000 cagtcaggag gcgaaacagaaggtggagaa ggaggctcag gcccgggagg 1050 ccaagctcca agctgaatgc tcccggcagacccagctagc gctggaggag 1100 aaggcggtgc tgcggaagga acgagacaac ctggccaaggagctggaaga 1150 gaagaagagg gaggcggagc agctcaggat ggagctggcc atcagaaact1200 cagccctgga cacctgcatc aagaccaagt cgcagccgat gatgccagtg 1250tcaaggccca tgggccctgt ccccaacccc cagcccatcg acccagctag 1300 cctggaggagttcaagagga agatcctgga gtcccagagg ccccctgcag 1350 gcatccctgt agccccatccagtggctgag gaggctccag gcctgaggac 1400 caagggatgg cccgactcgg cggtttgcggaggatgcagg gatatgctca 1450 cagcgcccga cacaaccccc tcccgccgcc cccaaccacccagggccacc 1500 atcagacaac tccctgcatg caaaccccta gtaccctctc acacccgcac1550 ccgcgcctca cgatccctca cccagagcac acggccgcgg agatgacgtc 1600acgcaagcaa cggcgctgac gtcacatatc accgtggtga tggcgtcacg 1650 tggccatgtagacgtcacga agagatatag cgatggcgtc gtgcagatgc 1700 agcacgtcgc acacagacatggggaacttg gcatgacgtc acaccgagat 1750 gcagcaacga cgtcacgggc catgtcgacgtcacacatat taatgtcaca 1800 cagacgcggc gatggcatca cacagacggt gatgatgtcacacacagaca 1850 cagtgacaac acacaccatg acaacgacac ctatagatat ggcaccaaca1900 tcacatgcac gcatgccctt tcacacacac tttctaccca attctcacct 1950agtgtcacgt tcccccgacc ctggcacacg ggccaaggta cccacaggat 2000 cccatcccctcccgcacagc cctgggcccc agcacctccc ctcctccagc 2050 ttcctggcct cccagccacttcctcacccc cagtgcctgg acccggaggt 2100 gagaacagga agccattcac ctccgctccttgagcgtgag tgtttccagg 2150 accccctcgg ggccctgagc cgggggtgag ggtcacctgttgtcgggagg 2200 ggagccactc cttctccccc aactcccagc cctgcctgtg gcccgttgaa2250 atgttggtgg cacttaataa atattagtaa atccttaaaa aaaaaaaaaa 2300aaaaaaaaaa aaaaaaa 2317 55 756 DNA Homo Sapien 55 cggacttggc ttgttagaaggctgaaagat gatggcagga atgaaaatcc 50 agcttgtatg catgctactc ctggctttcagctcctggag tctgtgctca 100 gattcagaag aggaaatgaa agcattagaa gcagatttcttgaccaatat 150 gcatacatca aagattagta aagcacatgt tccctcttgg aagatgactc200 tgctaaatgt ttgcagtctt gtaaataatt tgaacagccc agctgaggaa 250acaggagaag ttcatgaaga ggagcttgtt gcaagaagga aacttcctac 300 tgctttagatggctttagct tggaagcaat gttgacaata taccagctcc 350 acaaaatctg tcacagcagggcttttcaac actgggagtt aatccaggaa 400 gatattcttg atactggaaa tgacaaaaatggaaaggaag aagtcataaa 450 gagaaaaatt ccttatattc tgaaacggca gctgtatgagaataaaccca 500 gaagacccta catactcaaa agagattctt actattactg agagaataaa550 tcatttattt acatgtgatt gtgattcatc atcccttaat taaatatcaa 600attatatttg tgtgaaaatg tgacaaacac acttatctgt ctcttctaca 650 attgtggtttattgaatgtg tttttctgca ctaatagaaa ttagactaag 700 tgttttcaaa taaatctaaatcttcaaaaa aaaaaaaaaa aaatggggcc 750 gcaatt 756 56 3722 DNA Homo Sapien56 cgcggggcgc ggagtcggcg gggcctcgcg ggacgcgggc agtgcggaga 50 ccgcggcgctgaggacgcgg gagccgggag cgcacgcgcg gggtggagtt 100 cagcctactc tttcttagatgtgaaaggaa aggaagatca tttcatgcct 150 tgttgataaa ggttcagact tctgctgattcataaccatt tggctctgag 200 ctatgacaag agaggaaaca aaaagttaaa cttacaagcctgccataagt 250 gagaagcaaa cttccttgat aacatgcttt tgcgaagtgc aggaaaatta300 aatgtgggca ccaagaaaga ggatggtgag agtacagccc ccaccccccg 350tccaaaggtc ttgcgttgta aatgccacca ccattgtcca gaagactcag 400 tcaacaatatttgcagcaca gacggatatt gtttcacgat gatagaagag 450 gatgactctg ggttgcctgtggtcacttct ggttgcctag gactagaagg 500 ctcagatttt cagtgtcggg acactcccattcctcatcaa agaagatcaa 550 ttgaatgctg cacagaaagg aacgaatgta ataaagacctacaccctaca 600 ctgcctccat tgaaaaacag agattttgtt gatggaccta tacaccacag650 ggctttactt atatctgtga ctgtctgtag tttgctcttg gtccttatca 700tattattttg ttacttccgg tataaaagac aagaaaccag acctcgatac 750 agcattgggttagaacagga tgaaacttac attcctcctg gagaatccct 800 gagagactta attgagcagtctcagagctc aggaagtgga tcaggcctcc 850 ctctgctggt ccaaaggact atagctaagcagattcagat ggtgaaacag 900 attggaaaag gtcgctatgg ggaagtttgg atgggaaagtggcgtggcga 950 aaaggtagct gtgaaagtgt tcttcaccac agaggaagcc agctggttca1000 gagagacaga aatatatcag acagtgttga tgaggcatga aaacattttg 1050ggtttcattg ctgcagatat caaagggaca gggtcctgga cccagttgta 1100 cctaatcacagactatcatg aaaatggttc cctttatgat tatctgaagt 1150 ccaccaccct agacgctaaatcaatgctga agttagccta ctcttctgtc 1200 agtggcttat gtcatttaca cacagaaatctttagtactc aaggcaaacc 1250 agcaattgcc catcgagatc tgaaaagtaa aaacattctggtgaagaaaa 1300 atggaacttg ctgtattgct gacctgggcc tggctgttaa atttattagt1350 gatacaaatg aagttgacat accacctaac actcgagttg gcaccaaacg 1400ctatatgcct ccagaagtgt tggacgagag cttgaacaga aatcacttcc 1450 agtcttacatcatggctgac atgtatagtt ttggcctcat cctttgggag 1500 gttgctagga gatgtgtatcaggaggtata gtggaagaat accagcttcc 1550 ttatcatgac ctagtgccca gtgacccctcttatgaggac atgagggaga 1600 ttgtgtgcat caagaagtta cgcccctcat tcccaaaccggtggagcagt 1650 gatgagtgtc taaggcagat gggaaaactc atgacagaat gctgggctca1700 caatcctgca tcaaggctga cagccctgcg ggttaagaaa acacttgcca 1750aaatgtcaga gtcccaggac attaaactct gataggagag gaaaagtaag 1800 catctctgcagaaagccaac aggtactctt ctgtttgtgg gcagagcaaa 1850 agacatcaaa taagcatccacagtacaagc cttgaacatc gtcctgcttc 1900 ccagtgggtt cagacctcac ctttcagggagcgacctggg caaagacaga 1950 gaagctccca gaaggagaga ttgatccatg tctgtttgtaggacggagaa 2000 accgcttggg taacttgttc aagatatgat gcatgttgct ttctaagaaa2050 gccctgtatt ttgtgattgc cttttttttt ttttaagatg ctttcatttt 2100gccaaaataa aacagataat gtggatggtt taagggttat agtattatag 2150 tttaaataataacaacaaaa ttcttcccag gaactctgct ggaaggtaaa 2200 ttaaaatact tgtttttccattggtaaaat attgttgcac tctgtgaacc 2250 aaaagacagt ctaagttgga ggacatagaacggaactcat cttaaacata 2300 ctccccaccc cgtcttggcc tcctcagacc actttggccatccctgcatt 2350 tggggccgct atggtaatgt gaatgcactg ggtacaaaca ccgcctgtct2400 aggaccacat ttggaattcc tgcaggtggc cttttgcagc ttcaggcaat 2450atggaacaaa tgaaggttta tgtgactcta atagaagtaa ttgttgatag 2500 gtgtttttcagatccacttc tgtttctgat tgagttaggc atctctttca 2550 tggtaaaacc cttttcattaaacacaaaaa aagctttttt tttttttttt 2600 tttttttttt ttttttaatg tgcagaggattgacctgtgc atgcttttga 2650 tctctcattc aaaggatcaa tattaaataa aattgtcatgagctgtgttg 2700 aagacagggt gctttcaaat agaggtaatt tgctcttgtg ttgtaagagg2750 aacatgtcaa caaagatagg aaatgagggt gatcgtgcag atggcttgta 2800tcttatatat gcaaaggagc caatctcaga agcacaaaga aaaaagtgtg 2850 cataccttattttgtacaga taaagatgat gtctttttgt tattgtctgt 2900 ctgttttgta tgtgtctgagataagggata gagaggaaac atccgtcagg 2950 ctaatttaac tacattttat tttaaaaatagagaaacata acctctagat 3000 gggacagcag aggacagtta gtagaggcca caaactgttatgggctgctg 3050 tgttttgttc taaaatcaat atggttggag catgtatatc ttaggtgatc3100 atttcacatc ttaggaatgc ctactcattt tattttattc tagtgatgct 3150caattcacta tttaatttat tatattttct cttctgtggc acttatacaa 3200 aatatctcttcacctactta gttctacagg gttttaactt tggagcaaca 3250 tgaataaaat catcgagaaggccaatattg tttagcaaca tgaatacaat 3300 acagtttaaa gttgtacaca tcctgctcaactttattcat atacatttcc 3350 tttctgtggt tttcttttgc ttcttagaaa ttctgttagtggttagtaaa 3400 gaatttgaaa gtactttctc cttgctgttt tttttttttt ttaagacatt3450 cctcccagaa tactccaggg ggcagtgttt tataacacat tttccccact 3500gggtgattga aggatggagg atttttgaaa atttgacagc tacatgaaac 3550 atgagaaaacattttcctca cttctgaagt cggtttgcag ctggtaactt 3600 gttcatccag aaaacattctaaagcaatga gactttgtga gctgtgctta 3650 cagtttggga gaatcatgaa gattctttctatattttgca tttacttccc 3700 agtgcttcat agctgcattt tg 3722 57 837 PRT HomoSapien 57 Met Leu Arg Thr Ala Met Gly Leu Arg Ser Trp Leu Ala Ala Pro 15 10 15 Trp Gly Ala Leu Pro Pro Arg Pro Pro Leu Leu Leu Leu Leu Leu 2025 30 Leu Leu Leu Leu Leu Gln Pro Pro Pro Pro Thr Trp Ala Leu Ser 35 4045 Pro Arg Ile Ser Leu Pro Leu Gly Ser Glu Glu Arg Pro Phe Leu 50 55 60Arg Phe Glu Ala Glu His Ile Ser Asn Tyr Thr Ala Leu Leu Leu 65 70 75 SerArg Asp Gly Arg Thr Leu Tyr Val Gly Ala Arg Glu Ala Leu 80 85 90 Phe AlaLeu Ser Ser Asn Leu Ser Phe Leu Pro Gly Gly Glu Tyr 95 100 105 Gln GluLeu Leu Trp Gly Ala Asp Ala Glu Lys Lys Gln Gln Cys 110 115 120 Ser PheLys Gly Lys Asp Pro Gln Arg Asp Cys Gln Asn Tyr Ile 125 130 135 Lys IleLeu Leu Pro Leu Ser Gly Ser His Leu Phe Thr Cys Gly 140 145 150 Thr AlaAla Phe Ser Pro Met Cys Thr Tyr Ile Asn Met Glu Asn 155 160 165 Phe ThrLeu Ala Arg Asp Glu Lys Gly Asn Val Leu Leu Glu Asp 170 175 180 Gly LysGly Arg Cys Pro Phe Asp Pro Asn Phe Lys Ser Thr Ala 185 190 195 Leu ValVal Asp Gly Glu Leu Tyr Thr Gly Thr Val Ser Ser Phe 200 205 210 Gln GlyAsn Asp Pro Ala Ile Ser Arg Ser Gln Ser Leu Arg Pro 215 220 225 Thr LysThr Glu Ser Ser Leu Asn Trp Leu Gln Asp Pro Ala Phe 230 235 240 Val AlaSer Ala Tyr Ile Pro Glu Ser Leu Gly Ser Leu Gln Gly 245 250 255 Asp AspAsp Lys Ile Tyr Phe Phe Phe Ser Glu Thr Gly Gln Glu 260 265 270 Phe GluPhe Phe Glu Asn Thr Ile Val Ser Arg Ile Ala Arg Ile 275 280 285 Cys LysGly Asp Glu Gly Gly Glu Arg Val Leu Gln Gln Arg Trp 290 295 300 Thr SerPhe Leu Lys Ala Gln Leu Leu Cys Ser Arg Pro Asp Asp 305 310 315 Gly PhePro Phe Asn Val Leu Gln Asp Val Phe Thr Leu Ser Pro 320 325 330 Ser ProGln Asp Trp Arg Asp Thr Leu Phe Tyr Gly Val Phe Thr 335 340 345 Ser GlnTrp His Arg Gly Thr Thr Glu Gly Ser Ala Val Cys Val 350 355 360 Phe ThrMet Lys Asp Val Gln Arg Val Phe Ser Gly Leu Tyr Lys 365 370 375 Glu ValAsn Arg Glu Thr Gln Gln Trp Tyr Thr Val Thr His Pro 380 385 390 Val ProThr Pro Arg Pro Gly Ala Cys Ile Thr Asn Ser Ala Arg 395 400 405 Glu ArgLys Ile Asn Ser Ser Leu Gln Leu Pro Asp Arg Val Leu 410 415 420 Asn PheLeu Lys Asp His Phe Leu Met Asp Gly Gln Val Arg Ser 425 430 435 Arg MetLeu Leu Leu Gln Pro Gln Ala Arg Tyr Gln Arg Val Ala 440 445 450 Val HisArg Val Pro Gly Leu His His Thr Tyr Asp Val Leu Phe 455 460 465 Leu GlyThr Gly Asp Gly Arg Leu His Lys Ala Val Ser Val Gly 470 475 480 Pro ArgVal His Ile Ile Glu Glu Leu Gln Ile Phe Ser Ser Gly 485 490 495 Gln ProVal Gln Asn Leu Leu Leu Asp Thr His Arg Gly Leu Leu 500 505 510 Tyr AlaAla Ser His Ser Gly Val Val Gln Val Pro Met Ala Asn 515 520 525 Cys SerLeu Tyr Arg Ser Cys Gly Asp Cys Leu Leu Ala Arg Asp 530 535 540 Pro TyrCys Ala Trp Ser Gly Ser Ser Cys Lys His Val Ser Leu 545 550 555 Tyr GlnPro Gln Leu Ala Thr Arg Pro Trp Ile Gln Asp Ile Glu 560 565 570 Gly AlaSer Ala Lys Asp Leu Cys Ser Ala Ser Ser Val Val Ser 575 580 585 Pro SerPhe Val Pro Thr Gly Glu Lys Pro Cys Glu Gln Val Gln 590 595 600 Phe GlnPro Asn Thr Val Asn Thr Leu Ala Cys Pro Leu Leu Ser 605 610 615 Asn LeuAla Thr Arg Leu Trp Leu Arg Asn Gly Ala Pro Val Asn 620 625 630 Ala SerAla Ser Cys His Val Leu Pro Thr Gly Asp Leu Leu Leu 635 640 645 Val GlyThr Gln Gln Leu Gly Glu Phe Gln Cys Trp Ser Leu Glu 650 655 660 Glu GlyPhe Gln Gln Leu Val Ala Ser Tyr Cys Pro Glu Val Val 665 670 675 Glu AspGly Val Ala Asp Gln Thr Asp Glu Gly Gly Ser Val Pro 680 685 690 Val IleIle Ser Thr Ser Arg Val Ser Ala Pro Ala Gly Gly Lys 695 700 705 Ala SerTrp Gly Ala Asp Arg Ser Tyr Trp Lys Glu Phe Leu Val 710 715 720 Met CysThr Leu Phe Val Leu Ala Val Leu Leu Pro Val Leu Phe 725 730 735 Leu LeuTyr Arg His Arg Asn Ser Met Lys Val Phe Leu Lys Gln 740 745 750 Gly GluCys Ala Ser Val His Pro Lys Thr Cys Pro Val Val Leu 755 760 765 Pro ProGlu Thr Arg Pro Leu Asn Gly Leu Gly Pro Pro Ser Thr 770 775 780 Pro LeuAsp His Arg Gly Tyr Gln Ser Leu Ser Asp Ser Pro Pro 785 790 795 Gly AlaArg Val Phe Thr Glu Ser Glu Lys Arg Pro Leu Ser Ile 800 805 810 Gln AspSer Phe Val Glu Val Ser Pro Val Cys Pro Arg Pro Arg 815 820 825 Val ArgLeu Gly Ser Glu Ile Arg Asp Ser Val Val 830 835 58 188 PRT Homo Sapien58 Met Asp Cys Arg Lys Met Ala Arg Phe Ser Tyr Ser Val Ile Trp 1 5 10 15Ile Met Ala Ile Ser Lys Val Phe Glu Leu Gly Leu Val Ala Gly 20 25 30 LeuGly His Gln Glu Phe Ala Arg Pro Ser Arg Gly Tyr Leu Ala 35 40 45 Phe ArgAsp Asp Ser Ile Trp Pro Gln Glu Glu Pro Ala Ile Arg 50 55 60 Pro Arg SerSer Gln Arg Val Pro Pro Met Gly Ile Gln His Ser 65 70 75 Lys Glu Leu AsnArg Thr Cys Cys Leu Asn Gly Gly Thr Cys Met 80 85 90 Leu Gly Ser Phe CysAla Cys Pro Pro Ser Phe Tyr Gly Arg Asn 95 100 105 Cys Glu His Asp ValArg Lys Glu Asn Cys Gly Ser Val Pro His 110 115 120 Asp Thr Trp Leu ProLys Lys Cys Ser Leu Cys Lys Cys Trp His 125 130 135 Gly Gln Leu Arg CysPhe Pro Gln Ala Phe Leu Pro Gly Cys Asp 140 145 150 Gly Leu Val Met AspGlu His Leu Val Ala Ser Arg Thr Pro Glu 155 160 165 Leu Pro Pro Ser AlaArg Thr Thr Thr Phe Met Leu Val Gly Ile 170 175 180 Cys Leu Ser Ile GlnSer Tyr Tyr 185 59 80 PRT Homo Sapien 59 Met Ala Ala Arg Ala Leu Cys MetLeu Gly Leu Val Leu Ala Leu 1 5 10 15 Leu Ser Ser Ser Ser Ala Glu GluTyr Val Gly Leu Ser Ala Asn 20 25 30 Gln Cys Ala Val Pro Ala Lys Asp ArgVal Asp Cys Gly Tyr Pro 35 40 45 His Val Thr Pro Lys Glu Cys Asn Asn ArgGly Cys Cys Phe Asp 50 55 60 Ser Arg Ile Pro Gly Val Pro Trp Cys Phe LysPro Leu Gln Glu 65 70 75 Ala Glu Cys Thr Phe 80 60 314 PRT Homo Sapien60 Met Arg Ile Ala Val Ile Cys Phe Cys Leu Leu Gly Ile Thr Cys 1 5 10 15Ala Ile Pro Val Lys Gln Ala Asp Ser Gly Ser Ser Glu Glu Lys 20 25 30 GlnLeu Tyr Asn Lys Tyr Pro Asp Ala Val Ala Thr Trp Leu Asn 35 40 45 Pro AspPro Ser Gln Lys Gln Asn Leu Leu Ala Pro Gln Asn Ala 50 55 60 Val Ser SerGlu Glu Thr Asn Asp Phe Lys Gln Glu Thr Leu Pro 65 70 75 Ser Lys Ser AsnGlu Ser His Asp His Met Asp Asp Met Asp Asp 80 85 90 Glu Asp Asp Asp AspHis Val Asp Ser Gln Asp Ser Ile Asp Ser 95 100 105 Asn Asp Ser Asp AspVal Asp Asp Thr Asp Asp Ser His Gln Ser 110 115 120 Asp Glu Ser His HisSer Asp Glu Ser Asp Glu Leu Val Thr Asp 125 130 135 Phe Pro Thr Asp LeuPro Ala Thr Glu Val Phe Thr Pro Val Val 140 145 150 Pro Thr Val Asp ThrTyr Asp Gly Arg Gly Asp Ser Val Val Tyr 155 160 165 Gly Leu Arg Ser LysSer Lys Lys Phe Arg Arg Pro Asp Ile Gln 170 175 180 Tyr Pro Asp Ala ThrAsp Glu Asp Ile Thr Ser His Met Glu Ser 185 190 195 Glu Glu Leu Asn GlyAla Tyr Lys Ala Ile Pro Val Ala Gln Asp 200 205 210 Leu Asn Ala Pro SerAsp Trp Asp Ser Arg Gly Lys Asp Ser Tyr 215 220 225 Glu Thr Ser Gln LeuAsp Asp Gln Ser Ala Glu Thr His Ser His 230 235 240 Lys Gln Ser Arg LeuTyr Lys Arg Lys Ala Asn Asp Glu Ser Asn 245 250 255 Glu His Ser Asp ValIle Asp Ser Gln Glu Leu Ser Lys Val Ser 260 265 270 Arg Glu Phe His SerHis Glu Phe His Ser His Glu Asp Met Leu 275 280 285 Val Val Asp Pro LysSer Lys Glu Glu Asp Lys His Leu Lys Phe 290 295 300 Arg Ile Ser His GluLeu Asp Ser Ala Ser Ser Glu Val Asn 305 310 61 184 PRT Homo Sapien 61Met Ser Arg Thr Ala Tyr Thr Val Gly Ala Leu Leu Leu Leu Leu 1 5 10 15Gly Thr Leu Leu Pro Ala Ala Glu Gly Lys Lys Lys Gly Ser Gln 20 25 30 GlyAla Ile Pro Pro Pro Asp Lys Ala Gln His Asn Asp Ser Glu 35 40 45 Gln ThrGln Ser Pro Gln Gln Pro Gly Ser Arg Asn Arg Gly Arg 50 55 60 Gly Gln GlyArg Gly Thr Ala Met Pro Gly Glu Glu Val Leu Glu 65 70 75 Ser Ser Gln GluAla Leu His Val Thr Glu Arg Lys Tyr Leu Lys 80 85 90 Arg Asp Trp Cys LysThr Gln Pro Leu Lys Gln Thr Ile His Glu 95 100 105 Glu Gly Cys Asn SerArg Thr Ile Ile Asn Arg Phe Cys Tyr Gly 110 115 120 Gln Cys Asn Ser PheTyr Ile Pro Arg His Ile Arg Lys Glu Glu 125 130 135 Gly Ser Phe Gln SerCys Ser Phe Cys Lys Pro Lys Lys Phe Thr 140 145 150 Thr Met Met Val ThrLeu Asn Cys Pro Glu Leu Gln Pro Pro Thr 155 160 165 Lys Lys Lys Arg ValThr Arg Val Lys Gln Cys Arg Cys Ile Ser 170 175 180 Ile Asp Leu Asp 62460 PRT Homo Sapien 62 Met Phe Leu Ala Thr Leu Tyr Phe Ala Leu Pro LeuLeu Asp Leu 1 5 10 15 Leu Leu Ser Ala Glu Val Ser Gly Gly Asp Arg LeuAsp Cys Val 20 25 30 Lys Ala Ser Asp Gln Cys Leu Lys Glu Gln Ser Cys SerThr Lys 35 40 45 Tyr Arg Thr Leu Arg Gln Cys Val Ala Gly Lys Glu Thr AsnPhe 50 55 60 Ser Leu Ala Ser Gly Leu Glu Ala Lys Asp Glu Cys Arg Ser Ala65 70 75 Met Glu Ala Leu Lys Gln Lys Ser Leu Tyr Asn Cys Arg Cys Lys 8085 90 Arg Gly Met Lys Lys Glu Lys Asn Cys Leu Arg Ile Tyr Trp Ser 95 100105 Met Tyr Gln Ser Leu Gln Gly Asn Asp Leu Leu Glu Asp Ser Pro 110 115120 Tyr Glu Pro Val Asn Ser Arg Leu Ser Asp Ile Phe Arg Val Val 125 130135 Pro Phe Ile Ser Val Glu His Ile Pro Lys Gly Asn Asn Cys Leu 140 145150 Asp Ala Ala Lys Ala Cys Asn Leu Asp Asp Ile Cys Lys Lys Tyr 155 160165 Arg Ser Ala Tyr Ile Thr Pro Cys Thr Thr Ser Val Ser Asn Asp 170 175180 Val Cys Asn Arg Arg Lys Cys His Lys Ala Leu Arg Gln Phe Phe 185 190195 Asp Lys Val Pro Ala Lys His Ser Tyr Gly Met Leu Phe Cys Ser 200 205210 Cys Arg Asp Ile Ala Cys Thr Glu Arg Arg Arg Gln Thr Ile Val 215 220225 Pro Val Cys Ser Tyr Glu Glu Arg Glu Lys Pro Asn Cys Leu Asn 230 235240 Leu Gln Asp Ser Cys Lys Thr Asn Tyr Ile Cys Arg Ser Arg Leu 245 250255 Ala Asp Phe Phe Thr Asn Cys Gln Pro Glu Ser Arg Ser Val Ser 260 265270 Ser Cys Leu Lys Glu Asn Tyr Ala Asp Cys Leu Leu Ala Tyr Ser 275 280285 Gly Leu Ile Gly Thr Val Met Thr Pro Asn Tyr Ile Asp Ser Ser 290 295300 Ser Leu Ser Val Ala Pro Trp Cys Asp Cys Ser Asn Ser Gly Asn 305 310315 Asp Leu Glu Glu Cys Leu Lys Phe Leu Asn Phe Phe Lys Asp Asn 320 325330 Thr Cys Leu Lys Asn Ala Ile Gln Ala Phe Gly Asn Gly Ser Asp 335 340345 Val Thr Val Trp Gln Pro Ala Phe Pro Val Gln Thr Thr Thr Ala 350 355360 Thr Thr Thr Thr Ala Leu Arg Val Lys Asn Lys Pro Leu Gly Pro 365 370375 Ala Gly Ser Glu Asn Glu Ile Pro Thr His Val Leu Pro Pro Cys 380 385390 Ala Asn Leu Gln Ala Gln Lys Leu Lys Ser Asn Val Ser Gly Asn 395 400405 Thr His Leu Cys Ile Ser Asn Gly Asn Tyr Glu Lys Glu Gly Leu 410 415420 Gly Ala Ser Ser His Ile Thr Thr Lys Ser Met Ala Ala Pro Pro 425 430435 Ser Cys Gly Leu Ser Pro Leu Leu Val Leu Val Val Thr Ala Leu 440 445450 Ser Thr Leu Leu Ser Leu Thr Glu Thr Ser 455 460 63 143 PRT HomoSapien 63 Met Gln His Arg Gly Phe Leu Leu Leu Thr Leu Leu Ala Leu Leu 15 10 15 Ala Leu Thr Ser Ala Val Ala Lys Lys Lys Asp Lys Val Lys Lys 2025 30 Gly Gly Pro Gly Ser Glu Cys Ala Glu Trp Ala Trp Gly Pro Cys 35 4045 Thr Pro Ser Ser Lys Asp Cys Gly Val Gly Phe Arg Glu Gly Thr 50 55 60Cys Gly Ala Gln Thr Gln Arg Ile Arg Cys Arg Val Pro Cys Asn 65 70 75 TrpLys Lys Glu Phe Gly Ala Asp Cys Lys Tyr Lys Phe Glu Asn 80 85 90 Trp GlyAla Cys Asp Gly Gly Thr Gly Thr Lys Val Arg Gln Gly 95 100 105 Thr LeuLys Lys Ala Arg Tyr Asn Ala Gln Cys Gln Glu Thr Ile 110 115 120 Arg ValThr Lys Pro Cys Thr Pro Lys Thr Lys Ala Lys Ala Lys 125 130 135 Ala LysLys Gly Lys Gly Lys Asp 140 64 141 PRT Homo sapien 64 Met Trp Val LeuGly Ile Ala Ala Thr Phe Cys Gly Leu Phe Leu 1 5 10 15 Leu Pro Gly PheAla Leu Gln Ile Gln Cys Tyr Gln Cys Glu Glu 20 25 30 Phe Gln Leu Asn AsnAsp Cys Ser Ser Pro Glu Phe Ile Val Asn 35 40 45 Cys Thr Val Asn Val GlnAsp Met Cys Gln Lys Glu Val Met Glu 50 55 60 Gln Ser Ala Gly Ile Met TyrArg Lys Ser Cys Ala Ser Ser Ala 65 70 75 Ala Cys Leu Ile Ala Ser Ala GlyTyr Gln Ser Phe Cys Ser Pro 80 85 90 Gly Lys Leu Asn Ser Val Cys Ile SerCys Cys Asn Thr Pro Leu 95 100 105 Cys Asn Gly Pro Arg Pro Lys Lys ArgGly Ser Ser Ala Ser Ala 110 115 120 Leu Arg Pro Gly Leu Arg Thr Thr IleLeu Phe Leu Lys Leu Ala 125 130 135 Leu Phe Ser Ala His Cys 140 65 242PRT Homo Sapien 65 Met Lys Asn Ile Gly Leu Val Met Glu Trp Glu Ile ProGlu Ile 1 5 10 15 Ile Cys Thr Cys Ala Lys Leu Arg Leu Pro Pro Gln AlaThr Phe 20 25 30 Gln Val Leu Arg Gly Asn Gly Ala Ser Val Gly Thr Val LeuMet 35 40 45 Phe Arg Cys Pro Ser Asn His Gln Met Val Gly Ser Gly Leu Leu50 55 60 Thr Cys Thr Trp Lys Gly Ser Ile Ala Glu Trp Ser Ser Gly Ser 6570 75 Pro Val Cys Lys Leu Val Pro Pro His Glu Thr Phe Gly Phe Lys 80 8590 Val Ala Val Ile Ala Ser Ile Val Ser Cys Ala Ile Ile Leu Leu 95 100105 Met Ser Met Ala Phe Leu Thr Cys Cys Leu Leu Lys Cys Val Lys 110 115120 Lys Ser Lys Arg Arg Arg Ser Asn Arg Ser Ala Gln Leu Trp Ser 125 130135 Gln Leu Lys Asp Glu Asp Leu Glu Thr Val Gln Ala Ala Tyr Leu 140 145150 Gly Leu Lys His Phe Asn Lys Pro Val Ser Gly Pro Ser Gln Ala 155 160165 His Asp Asn His Ser Phe Thr Thr Asp His Gly Glu Ser Thr Ser 170 175180 Lys Leu Ala Ser Val Thr Arg Ser Val Asp Lys Asp Pro Gly Ile 185 190195 Pro Arg Ala Leu Ser Leu Ser Gly Ser Ser Ser Ser Pro Gln Ala 200 205210 Gln Val Met Val His Met Ala Asn Pro Arg Gln Pro Leu Pro Ala 215 220225 Ser Gly Leu Ala Thr Gly Met Pro Gln Gln Pro Ala Ala Tyr Ala 230 235240 Leu Gly 66 672 PRT Homo sapien 66 Asp Cys Thr Gly Asp Gly Pro TrpGln Ser Asn Leu Ala Pro Ser 1 5 10 15 Gln Leu Glu Tyr Tyr Ala Ser SerPro Asp Glu Lys Ala Leu Val 20 25 30 Glu Ala Ala Ala Arg Ile Gly Ile ValPhe Ile Gly Asn Ser Glu 35 40 45 Glu Thr Met Glu Val Lys Thr Leu Gly LysLeu Glu Arg Tyr Lys 50 55 60 Leu Leu His Ile Leu Glu Phe Asp Ser Asp ArgArg Arg Met Ser 65 70 75 Val Ile Val Gln Ala Pro Ser Gly Glu Lys Leu LeuPhe Ala Lys 80 85 90 Gly Ala Glu Ser Ser Ile Leu Pro Lys Cys Ile Gly GlyGlu Ile 95 100 105 Glu Lys Thr Arg Ile His Val Asp Glu Phe Ala Leu LysGly Leu 110 115 120 Arg Thr Leu Cys Ile Ala Tyr Arg Lys Phe Thr Ser LysGlu Tyr 125 130 135 Glu Glu Ile Asp Lys Arg Ile Phe Glu Ala Arg Thr AlaLeu Gln 140 145 150 Gln Arg Glu Glu Lys Leu Ala Ala Val Phe Gln Phe IleGlu Lys 155 160 165 Asp Leu Ile Leu Leu Gly Ala Thr Ala Val Glu Asp ArgLeu Gln 170 175 180 Asp Lys Val Arg Glu Thr Ile Glu Ala Leu Arg Met AlaGly Ile 185 190 195 Lys Val Trp Val Leu Thr Gly Asp Lys His Glu Thr AlaVal Ser 200 205 210 Val Ser Leu Ser Cys Gly His Phe His Arg Thr Met AsnIle Leu 215 220 225 Glu Leu Ile Asn Gln Lys Ser Asp Ser Glu Cys Ala GluGln Leu 230 235 240 Arg Gln Leu Ala Arg Arg Ile Thr Glu Asp His Val IleGln His 245 250 255 Gly Leu Val Val Asp Gly Thr Ser Leu Ser Leu Ala LeuArg Glu 260 265 270 His Glu Lys Leu Phe Met Glu Val Cys Arg Asn Cys SerAla Val 275 280 285 Leu Cys Cys Arg Met Ala Pro Leu Gln Lys Ala Lys ValIle Arg 290 295 300 Leu Ile Lys Ile Ser Pro Glu Lys Pro Ile Thr Leu AlaVal Gly 305 310 315 Asp Gly Ala Asn Asp Val Ser Met Ile Gln Glu Ala HisVal Gly 320 325 330 Ile Gly Ile Met Gly Lys Glu Gly Arg Gln Ala Ala ArgAsn Ser 335 340 345 Asp Tyr Ala Ile Ala Arg Phe Lys Phe Leu Ser Lys LeuLeu Phe 350 355 360 Val His Gly His Phe Tyr Tyr Ile Arg Ile Ala Thr LeuVal Gln 365 370 375 Tyr Phe Phe Tyr Lys Asn Val Cys Phe Ile Thr Pro GlnPhe Leu 380 385 390 Tyr Gln Phe Tyr Cys Leu Phe Ser Gln Gln Thr Leu TyrAsp Ser 395 400 405 Val Tyr Leu Thr Leu Tyr Asn Ile Cys Phe Thr Ser LeuPro Ile 410 415 420 Leu Ile Tyr Ser Leu Leu Glu Gln His Val Asp Pro HisVal Leu 425 430 435 Gln Asn Lys Pro Thr Leu Tyr Arg Asp Ile Ser Lys AsnArg Leu 440 445 450 Leu Ser Ile Lys Thr Phe Leu Tyr Trp Thr Ile Leu GlyPhe Ser 455 460 465 His Ala Phe Ile Phe Phe Phe Gly Ser Tyr Leu Leu IleGly Lys 470 475 480 Asp Thr Ser Leu Leu Gly Asn Gly Gln Met Phe Gly AsnTrp Thr 485 490 495 Phe Gly Thr Leu Val Phe Thr Val Met Val Ile Thr ValThr Val 500 505 510 Lys Met Ala Leu Glu Thr His Phe Trp Thr Trp Ile AsnHis Leu 515 520 525 Val Thr Trp Gly Ser Ile Ile Phe Tyr Phe Val Phe SerLeu Phe 530 535 540 Tyr Gly Gly Ile Leu Trp Pro Phe Leu Gly Ser Gln AsnMet Tyr 545 550 555 Phe Val Phe Ile Gln Leu Leu Ser Ser Gly Ser Ala TrpPhe Ala 560 565 570 Ile Ile Leu Met Val Val Thr Cys Leu Phe Leu Asp IleIle Lys 575 580 585 Lys Val Phe Asp Arg His Leu His Pro Thr Ser Thr GluLys Ala 590 595 600 Gln Leu Thr Glu Thr Asn Ala Gly Ile Lys Cys Leu AspSer Met 605 610 615 Cys Cys Phe Pro Glu Gly Glu Ala Ala Cys Ala Ser ValGly Arg 620 625 630 Met Leu Glu Arg Val Ile Gly Arg Cys Ser Pro Thr HisIle Ser 635 640 645 Arg Ser Trp Ser Ala Ser Asp Pro Phe Tyr Thr Asn AspArg Ser 650 655 660 Ile Leu Thr Leu Ser Thr Met Asp Ser Ser Thr Cys 665670 67 877 PRT Homo Sapien 67 Met Trp Glu Glu Glu Asp Ile Ala Ile LeuPhe Asn Lys Glu Pro 1 5 10 15 Gly Lys Thr Glu Asn Ile Glu Asn Asn LeuSer Ser Asn His Arg 20 25 30 Arg Ser Cys Arg Arg Ser Glu Glu Ser Asp AspAsp Leu Asp Phe 35 40 45 Asp Ile Gly Leu Glu Asn Thr Gly Gly Asp Pro GlnIle Leu Arg 50 55 60 Phe Ile Ser Asp Phe Leu Ala Phe Leu Val Leu Tyr AsnPhe Ile 65 70 75 Ile Pro Ile Ser Leu Tyr Val Thr Val Glu Met Gln Lys PheLeu 80 85 90 Gly Ser Phe Phe Ile Gly Trp Asp Leu Asp Leu Tyr His Glu Glu95 100 105 Ser Asp Gln Lys Ala Gln Val Asn Thr Ser Asp Leu Asn Glu Glu110 115 120 Leu Gly Gln Val Glu Tyr Val Phe Thr Asp Lys Thr Gly Thr Leu125 130 135 Thr Glu Asn Glu Met Gln Phe Arg Glu Cys Ser Ile Asn Gly Met140 145 150 Lys Tyr Gln Glu Ile Asn Gly Arg Leu Val Pro Glu Gly Pro Thr155 160 165 Pro Asp Ser Ser Glu Gly Asn Leu Ser Tyr Leu Ser Ser Leu Ser170 175 180 His Leu Asn Asn Leu Ser His Leu Thr Thr Ser Ser Ser Phe Arg185 190 195 Thr Ser Pro Glu Asn Glu Thr Glu Leu Ile Lys Glu His Asp Leu200 205 210 Phe Phe Lys Ala Val Ser Leu Cys His Thr Val Gln Ile Ser Asn215 220 225 Val Gln Thr Asp Cys Thr Gly Asp Gly Pro Trp Gln Ser Asn Leu230 235 240 Ala Pro Ser Gln Leu Glu Tyr Tyr Ala Ser Ser Pro Asp Glu Lys245 250 255 Ala Leu Val Glu Ala Ala Ala Arg Tyr Lys Leu Leu His Ile Leu260 265 270 Glu Phe Asp Ser Asp Arg Arg Arg Met Ser Val Ile Val Gln Ala275 280 285 Pro Ser Gly Glu Lys Leu Leu Phe Ala Lys Gly Ala Glu Ser Ser290 295 300 Ile Leu Pro Lys Cys Ile Gly Gly Glu Ile Glu Lys Thr Arg Ile305 310 315 His Val Asp Glu Phe Ala Leu Lys Gly Leu Arg Thr Leu Cys Ile320 325 330 Ala Tyr Arg Lys Phe Thr Ser Lys Glu Tyr Glu Glu Ile Asp Lys335 340 345 Arg Ile Phe Glu Ala Arg Thr Ala Leu Gln Gln Arg Glu Glu Lys350 355 360 Leu Ala Ala Val Phe Gln Phe Ile Glu Lys Asp Leu Ile Leu Leu365 370 375 Gly Ala Thr Ala Val Glu Asp Arg Leu Gln Asp Lys Val Arg Glu380 385 390 Thr Ile Glu Ala Leu Arg Met Ala Gly Ile Lys Val Trp Val Leu395 400 405 Thr Gly Asp Lys His Glu Thr Ala Val Ser Val Ser Leu Ser Cys410 415 420 Gly His Phe His Arg Thr Met Asn Ile Leu Glu Leu Ile Asn Gln425 430 435 Lys Ser Asp Ser Glu Cys Ala Glu Gln Leu Arg Gln Leu Ala Arg440 445 450 Arg Ile Thr Glu Asp His Val Ile Gln His Gly Leu Val Val Asp455 460 465 Gly Thr Ser Leu Ser Leu Ala Leu Arg Glu His Glu Lys Leu Phe470 475 480 Met Glu Val Cys Arg Asn Cys Ser Ala Val Leu Cys Cys Arg Met485 490 495 Ala Pro Leu Gln Lys Ala Lys Val Ile Arg Leu Ile Lys Ile Ser500 505 510 Pro Glu Lys Pro Ile Thr Leu Ala Val Gly Asp Gly Ala Asn Asp515 520 525 Val Ser Met Ile Gln Glu Ala His Val Gly Ile Gly Ile Met Gly530 535 540 Lys Glu Gly Arg Gln Ala Ala Arg Asn Ser Asp Tyr Ala Ile Ala545 550 555 Arg Phe Lys Phe Leu Ser Lys Leu Leu Phe Val His Gly His Phe560 565 570 Tyr Tyr Ile Arg Ile Ala Thr Leu Val Gln Tyr Phe Phe Tyr Lys575 580 585 Asn Val Cys Phe Ile Thr Pro Gln Phe Leu Tyr Gln Phe Tyr Cys590 595 600 Leu Phe Ser Gln Gln Thr Leu Tyr Asp Ser Val Tyr Leu Thr Leu605 610 615 Tyr Asn Ile Cys Phe Thr Ser Leu Pro Ile Leu Ile Tyr Ser Leu620 625 630 Leu Glu Gln His Val Asp Pro His Val Leu Gln Asn Lys Pro Thr635 640 645 Leu Tyr Arg Asp Ile Ser Lys Asn Arg Leu Leu Ser Ile Lys Thr650 655 660 Phe Leu Tyr Trp Thr Ile Leu Gly Phe Ser His Ala Phe Ile Phe665 670 675 Phe Phe Gly Ser Tyr Leu Leu Ile Gly Lys Asp Thr Ser Leu Leu680 685 690 Gly Asn Gly Gln Met Phe Gly Asn Trp Thr Phe Gly Thr Leu Val695 700 705 Phe Thr Val Met Val Ile Thr Val Thr Val Lys Met Ala Leu Glu710 715 720 Thr His Phe Trp Thr Trp Ile Asn His Leu Val Thr Trp Gly Ser725 730 735 Ile Ile Phe Tyr Phe Val Phe Ser Leu Phe Tyr Gly Gly Ile Leu740 745 750 Trp Pro Phe Leu Gly Ser Gln Asn Met Tyr Phe Val Phe Ile Gln755 760 765 Leu Leu Ser Ser Gly Ser Ala Trp Phe Ala Ile Ile Leu Met Val770 775 780 Val Thr Cys Leu Phe Leu Asp Ile Ile Lys Lys Val Phe Asp Arg785 790 795 His Leu His Pro Thr Ser Thr Glu Lys Ala Gln Leu Thr Glu Thr800 805 810 Asn Ala Gly Ile Lys Cys Leu Asp Ser Met Cys Cys Phe Pro Glu815 820 825 Gly Glu Ala Ala Cys Ala Ser Val Gly Arg Met Leu Glu Arg Val830 835 840 Ile Gly Arg Cys Ser Pro Thr His Ile Ser Arg Ser Trp Ser Ala845 850 855 Ser Asp Pro Phe Tyr Thr Asn Asp Arg Ser Ile Leu Thr Leu Ser860 865 870 Thr Met Asp Ser Ser Thr Cys 875 68 63 PRT Homo Sapien 68 MetLys His Val Leu Asn Leu Tyr Leu Leu Gly Val Val Leu Thr 1 5 10 15 LeuLeu Ser Ile Phe Val Arg Val Met Glu Ser Leu Glu Gly Leu 20 25 30 Leu GluSer Pro Ser Pro Gly Thr Ser Trp Thr Thr Arg Ser Gln 35 40 45 Leu Ala AsnThr Glu Pro Thr Lys Gly Leu Pro Asp His Pro Ser 50 55 60 Arg Ser Met 69137 PRT Homo Sapien unsure 101, 136 unknown amino acid 69 Met Lys ThrGly Leu Phe Phe Leu Cys Leu Leu Gly Thr Ala Ala 1 5 10 15 Ala Ile ProThr Asn Ala Arg Leu Leu Ser Asp His Ser Lys Pro 20 25 30 Thr Ala Glu ThrVal Ala Pro Asp Asn Thr Ala Ile Pro Ser Leu 35 40 45 Arg Ala Glu Asp GluGlu Asn Glu Lys Glu Thr Ala Val Ser Thr 50 55 60 Glu Asp Asp Ser His HisLys Ala Glu Lys Ser Ser Val Leu Lys 65 70 75 Ser Lys Glu Glu Ser His GluGln Ser Ala Glu Gln Gly Lys Ser 80 85 90 Ser Ser Gln Glu Leu Gly Leu LysAsp Gln Xaa Asp Ser Asp Gly 95 100 105 Asp Leu Ser Val Asn Leu Glu TyrAla Pro Thr Glu Gly Thr Leu 110 115 120 Asp Ile Lys Glu Asp Met Ser GluPro Gln Glu Lys Asn Ser Gln 125 130 135 Xaa His 70 318 PRT Homo Sapien70 Met Ala Pro Trp Ala Glu Ala Glu His Ser Ala Leu Asn Pro Leu 1 5 10 15Arg Ala Val Trp Leu Thr Leu Thr Ala Ala Phe Leu Leu Thr Leu 20 25 30 LeuLeu Gln Leu Leu Pro Pro Gly Leu Leu Pro Gly Cys Ala Ile 35 40 45 Phe GlnAsp Leu Ile Arg Tyr Gly Lys Thr Lys Cys Gly Glu Pro 50 55 60 Ser Arg ProAla Ala Cys Arg Ala Phe Asp Val Pro Lys Arg Tyr 65 70 75 Phe Ser His PheTyr Ile Ile Ser Val Leu Trp Asn Gly Phe Leu 80 85 90 Leu Trp Cys Leu ThrGln Ser Leu Phe Leu Gly Ala Pro Phe Pro 95 100 105 Ser Trp Leu His GlyLeu Leu Arg Ile Leu Gly Ala Ala Gln Phe 110 115 120 Gln Gly Gly Glu LeuAla Leu Ser Ala Phe Leu Val Leu Val Phe 125 130 135 Leu Trp Leu His SerLeu Arg Arg Leu Phe Glu Cys Leu Tyr Val 140 145 150 Ser Val Phe Ser AsnVal Met Ile His Val Val Gln Tyr Cys Phe 155 160 165 Gly Leu Val Tyr TyrVal Leu Val Gly Leu Thr Val Leu Ser Gln 170 175 180 Val Pro Met Asp GlyArg Asn Ala Tyr Ile Thr Gly Lys Asn Leu 185 190 195 Leu Met Gln Ala ArgTrp Phe His Ile Leu Gly Met Met Met Phe 200 205 210 Ile Trp Ser Ser AlaHis Gln Tyr Lys Cys His Val Ile Leu Gly 215 220 225 Asn Leu Arg Lys AsnLys Ala Gly Val Val Ile His Cys Asn His 230 235 240 Arg Ile Pro Phe GlyAsp Trp Phe Glu Tyr Val Ser Ser Pro Asn 245 250 255 Tyr Leu Ala Glu LeuMet Ile Tyr Val Ser Met Ala Val Thr Phe 260 265 270 Gly Phe His Asn LeuThr Trp Trp Leu Val Val Thr Asn Val Phe 275 280 285 Phe Asn Gln Ala LeuSer Ala Phe Leu Ser His Gln Phe Tyr Lys 290 295 300 Ser Lys Phe Val SerTyr Pro Lys His Arg Lys Ala Phe Leu Pro 305 310 315 Phe Leu Phe 71 426PRT Homo sapien 71 Met Pro Leu Leu Trp Leu Arg Gly Phe Leu Leu Ala SerCys Trp 1 5 10 15 Ile Ile Val Arg Ser Ser Pro Thr Pro Gly Ser Glu GlyHis Ser 20 25 30 Ala Ala Pro Asp Cys Pro Ser Cys Ala Leu Ala Ala Leu ProLys 35 40 45 Asp Val Pro Asn Ser Gln Pro Glu Met Val Glu Ala Val Lys Lys50 55 60 His Ile Leu Asn Met Leu His Leu Lys Lys Arg Pro Asp Val Thr 6570 75 Gln Pro Val Pro Lys Ala Ala Leu Leu Asn Ala Ile Arg Lys Leu 80 8590 His Val Gly Lys Val Gly Glu Asn Gly Tyr Val Glu Ile Glu Asp 95 100105 Asp Ile Gly Arg Arg Ala Glu Met Asn Glu Leu Met Glu Gln Thr 110 115120 Ser Glu Ile Ile Thr Phe Ala Glu Ser Gly Thr Ala Arg Lys Thr 125 130135 Leu His Phe Glu Ile Ser Lys Glu Gly Ser Asp Leu Ser Val Val 140 145150 Glu Arg Ala Glu Val Trp Leu Phe Leu Lys Val Pro Lys Ala Asn 155 160165 Arg Thr Arg Thr Lys Val Thr Ile Arg Leu Phe Gln Gln Gln Lys 170 175180 His Pro Gln Gly Ser Leu Asp Thr Gly Glu Glu Ala Glu Glu Val 185 190195 Gly Leu Lys Gly Glu Arg Ser Glu Leu Leu Leu Ser Glu Lys Val 200 205210 Val Asp Ala Arg Lys Ser Thr Trp His Val Phe Pro Val Ser Ser 215 220225 Ser Ile Gln Arg Leu Leu Asp Gln Gly Lys Ser Ser Leu Asp Val 230 235240 Arg Ile Ala Cys Glu Gln Cys Gln Glu Ser Gly Ala Ser Leu Val 245 250255 Leu Leu Gly Lys Lys Lys Lys Lys Glu Glu Glu Gly Glu Gly Lys 260 265270 Lys Lys Gly Gly Gly Glu Gly Gly Ala Gly Ala Asp Glu Glu Lys 275 280285 Glu Gln Ser His Arg Pro Phe Leu Met Leu Gln Ala Arg Gln Ser 290 295300 Glu Asp His Pro His Arg Arg Arg Arg Arg Gly Leu Glu Cys Asp 305 310315 Gly Lys Val Asn Ile Cys Cys Lys Lys Gln Phe Phe Val Ser Phe 320 325330 Lys Asp Ile Gly Trp Asn Asp Trp Ile Ile Ala Pro Ser Gly Tyr 335 340345 His Ala Asn Tyr Cys Glu Gly Glu Cys Pro Ser His Ile Ala Gly 350 355360 Thr Ser Gly Ser Ser Leu Ser Phe His Ser Thr Val Ile Asn His 365 370375 Tyr Arg Met Arg Gly His Ser Pro Phe Ala Asn Leu Lys Ser Cys 380 385390 Cys Val Pro Thr Lys Leu Arg Pro Met Ser Met Leu Tyr Tyr Asp 395 400405 Asp Gly Gln Asn Ile Ile Lys Lys Asp Ile Gln Asn Met Ile Val 410 415420 Glu Glu Cys Gly Cys Ser 425 72 238 PRT Homo Sapien 72 Met Ala AlaAla Pro Leu Leu Leu Leu Leu Leu Leu Val Pro Val 1 5 10 15 Pro Leu LeuPro Leu Leu Ala Gln Gly Pro Gly Gly Ala Leu Gly 20 25 30 Asn Arg His AlaVal Tyr Trp Asn Ser Ser Asn Gln His Leu Arg 35 40 45 Arg Glu Gly Tyr ThrVal Gln Val Asn Val Asn Asp Tyr Leu Asp 50 55 60 Ile Tyr Cys Pro His TyrAsn Ser Ser Gly Val Gly Pro Gly Ala 65 70 75 Gly Pro Gly Pro Gly Gly GlyAla Glu Gln Tyr Val Leu Tyr Met 80 85 90 Val Ser Arg Asn Gly Tyr Arg ThrCys Asn Ala Ser Gln Gly Phe 95 100 105 Lys Arg Trp Glu Cys Asn Arg ProHis Ala Pro His Ser Pro Ile 110 115 120 Lys Phe Ser Glu Lys Phe Gln ArgTyr Ser Ala Phe Ser Leu Gly 125 130 135 Tyr Glu Phe His Ala Gly His GluTyr Tyr Tyr Ile Ser Thr Pro 140 145 150 Thr His Asn Leu His Trp Lys CysLeu Arg Met Lys Val Phe Val 155 160 165 Cys Cys Ala Ser Thr Ser His SerGly Glu Lys Pro Val Pro Thr 170 175 180 Leu Pro Gln Phe Thr Met Gly ProAsn Val Lys Ile Asn Val Leu 185 190 195 Glu Asp Phe Glu Gly Glu Asn ProGln Val Pro Lys Leu Glu Lys 200 205 210 Ser Ile Ser Gly Thr Ser Pro LysArg Glu His Leu Pro Leu Ala 215 220 225 Val Gly Ile Ala Phe Phe Leu MetThr Phe Leu Ala Ser 230 235 73 541 PRT Homo Sapien 73 Met Gly His SerPro Pro Val Leu Pro Leu Cys Ala Ser Val Ser 1 5 10 15 Leu Leu Gly GlyLeu Thr Phe Gly Tyr Glu Leu Ala Val Ile Ser 20 25 30 Gly Ala Leu Leu ProLeu Gln Leu Asp Phe Gly Leu Ser Cys Leu 35 40 45 Glu Gln Glu Phe Leu ValGly Ser Leu Leu Leu Gly Ala Leu Leu 50 55 60 Ala Ser Leu Val Gly Gly PheLeu Ile Asp Cys Tyr Gly Arg Lys 65 70 75 Gln Ala Ile Leu Gly Ser Asn LeuVal Leu Leu Ala Gly Ser Leu 80 85 90 Thr Leu Gly Leu Ala Gly Ser Leu AlaTrp Leu Val Leu Gly Arg 95 100 105 Ala Val Val Gly Phe Ala Ile Ser LeuSer Ser Met Ala Cys Cys 110 115 120 Ile Tyr Val Ser Glu Leu Val Gly ProArg Gln Arg Gly Val Leu 125 130 135 Val Ser Leu Tyr Glu Ala Gly Ile ThrVal Gly Ile Leu Leu Ser 140 145 150 Tyr Ala Leu Asn Tyr Ala Leu Ala GlyThr Pro Trp Gly Trp Arg 155 160 165 His Met Phe Gly Trp Ala Thr Ala ProAla Val Leu Gln Ser Leu 170 175 180 Ser Leu Leu Phe Leu Pro Ala Gly ThrAsp Glu Thr Ala Thr His 185 190 195 Lys Asp Leu Ile Pro Leu Gln Gly GlyGlu Ala Pro Lys Leu Gly 200 205 210 Pro Gly Arg Pro Arg Tyr Ser Phe LeuAsp Leu Phe Arg Ala Arg 215 220 225 Asp Asn Met Arg Gly Arg Thr Thr ValGly Leu Gly Leu Val Leu 230 235 240 Phe Gln Gln Leu Thr Gly Gln Pro AsnVal Leu Cys Tyr Ala Ser 245 250 255 Thr Ile Phe Ser Ser Val Gly Phe HisGly Gly Ser Ser Ala Val 260 265 270 Leu Ala Ser Val Gly Leu Gly Ala ValLys Val Ala Ala Thr Leu 275 280 285 Thr Ala Met Gly Leu Val Asp Arg AlaGly Arg Arg Ala Leu Leu 290 295 300 Leu Ala Gly Cys Ala Leu Met Ala LeuSer Val Ser Gly Ile Gly 305 310 315 Leu Val Ser Phe Ala Val Pro Met AspSer Gly Pro Ser Cys Leu 320 325 330 Ala Val Pro Asn Ala Thr Gly Gln ThrGly Leu Pro Gly Asp Ser 335 340 345 Gly Leu Leu Gln Asp Ser Ser Leu ProPro Ile Pro Arg Thr Asn 350 355 360 Glu Asp Gln Arg Glu Pro Ile Leu SerThr Ala Lys Lys Thr Lys 365 370 375 Pro His Pro Arg Ser Gly Asp Pro SerAla Pro Pro Arg Leu Ala 380 385 390 Leu Ser Ser Ala Leu Pro Gly Pro ProLeu Pro Ala Arg Gly His 395 400 405 Ala Leu Leu Arg Trp Thr Ala Leu LeuCys Leu Met Val Phe Val 410 415 420 Ser Ala Phe Ser Phe Gly Phe Gly ProVal Thr Trp Leu Val Leu 425 430 435 Ser Glu Ile Tyr Pro Val Glu Ile ArgGly Arg Ala Phe Ala Phe 440 445 450 Cys Asn Ser Phe Asn Trp Ala Ala AsnLeu Phe Ile Ser Leu Ser 455 460 465 Phe Leu Asp Leu Ile Gly Thr Ile GlyLeu Ser Trp Thr Phe Leu 470 475 480 Leu Tyr Gly Leu Thr Ala Val Leu GlyLeu Gly Phe Ile Tyr Leu 485 490 495 Phe Val Pro Glu Thr Lys Gly Gln SerLeu Ala Glu Ile Asp Gln 500 505 510 Gln Phe Gln Lys Arg Arg Phe Thr LeuSer Phe Gly His Arg Gln 515 520 525 Asn Ser Thr Gly Ile Pro Tyr Ser ArgIle Glu Ile Ser Ala Ala 530 535 540 Ser 74 1114 PRT Homo Sapien 74 MetAla Lys Ala Thr Ser Gly Ala Ala Gly Leu Arg Leu Leu Leu 1 5 10 15 LeuLeu Leu Leu Pro Leu Leu Gly Lys Val Ala Leu Gly Leu Tyr 20 25 30 Phe SerArg Asp Ala Tyr Trp Glu Lys Leu Tyr Val Asp Gln Ala 35 40 45 Ala Gly ThrPro Leu Leu Tyr Val His Ala Leu Arg Asp Ala Pro 50 55 60 Glu Glu Val ProSer Phe Arg Leu Gly Gln His Leu Tyr Gly Thr 65 70 75 Tyr Arg Thr Arg LeuHis Glu Asn Asn Trp Ile Cys Ile Gln Glu 80 85 90 Asp Thr Gly Leu Leu TyrLeu Asn Arg Ser Leu Asp His Ser Ser 95 100 105 Trp Glu Lys Leu Ser ValArg Asn Arg Gly Phe Pro Leu Leu Thr 110 115 120 Val Tyr Leu Lys Val PheLeu Ser Pro Thr Ser Leu Arg Glu Gly 125 130 135 Glu Cys Gln Trp Pro GlyCys Ala Arg Val Tyr Phe Ser Phe Phe 140 145 150 Asn Thr Ser Phe Pro AlaCys Ser Ser Leu Lys Pro Arg Glu Leu 155 160 165 Cys Phe Pro Glu Thr ArgPro Ser Phe Arg Ile Arg Glu Asn Arg 170 175 180 Pro Pro Gly Thr Phe HisGln Phe Arg Leu Leu Pro Val Gln Phe 185 190 195 Leu Cys Pro Asn Ile SerVal Ala Tyr Arg Leu Leu Glu Gly Glu 200 205 210 Gly Leu Pro Phe Arg CysAla Pro Asp Ser Leu Glu Val Ser Thr 215 220 225 Arg Trp Ala Leu Asp ArgGlu Gln Arg Glu Lys Tyr Glu Leu Val 230 235 240 Ala Val Cys Thr Val HisAla Gly Ala Arg Glu Glu Val Val Met 245 250 255 Val Pro Phe Pro Val ThrVal Tyr Asp Glu Asp Asp Ser Ala Pro 260 265 270 Thr Phe Pro Ala Gly ValAsp Thr Ala Ser Ala Val Val Glu Phe 275 280 285 Lys Arg Lys Glu Asp ThrVal Val Ala Thr Leu Arg Val Phe Asp 290 295 300 Ala Asp Val Val Pro AlaSer Gly Glu Leu Val Arg Arg Tyr Thr 305 310 315 Ser Thr Leu Leu Pro GlyAsp Thr Trp Ala Gln Gln Thr Phe Arg 320 325 330 Val Glu His Trp Pro AsnGlu Thr Ser Val Gln Ala Asn Gly Ser 335 340 345 Phe Val Arg Ala Thr ValHis Asp Tyr Arg Leu Val Leu Asn Arg 350 355 360 Asn Leu Ser Ile Ser GluAsn Arg Thr Met Gln Leu Ala Val Leu 365 370 375 Val Asn Asp Ser Asp PheGln Gly Pro Gly Ala Gly Val Leu Leu 380 385 390 Leu His Phe Asn Val SerVal Leu Pro Val Ser Leu His Leu Pro 395 400 405 Ser Thr Tyr Ser Leu SerVal Ser Arg Arg Ala Arg Arg Phe Ala 410 415 420 Gln Ile Gly Lys Val CysVal Glu Asn Cys Gln Ala Phe Ser Gly 425 430 435 Ile Asn Val Gln Tyr LysLeu His Ser Ser Gly Ala Asn Cys Ser 440 445 450 Thr Leu Gly Val Val ThrSer Ala Glu Asp Thr Ser Gly Ile Leu 455 460 465 Phe Val Asn Asp Thr LysAla Leu Arg Arg Pro Lys Cys Ala Glu 470 475 480 Leu His Tyr Met Val ValAla Thr Asp Gln Gln Thr Ser Arg Gln 485 490 495 Ala Gln Ala Gln Leu LeuVal Thr Val Glu Gly Ser Tyr Val Ala 500 505 510 Glu Glu Ala Gly Cys ProLeu Ser Cys Ala Val Ser Lys Arg Arg 515 520 525 Leu Glu Cys Glu Glu CysGly Gly Leu Gly Ser Pro Thr Gly Arg 530 535 540 Cys Glu Trp Arg Gln GlyAsp Gly Lys Gly Ile Thr Arg Asn Phe 545 550 555 Ser Thr Cys Ser Pro SerThr Lys Thr Cys Pro Asp Gly His Cys 560 565 570 Asp Val Val Glu Thr GlnAsp Ile Asn Ile Cys Pro Gln Asp Cys 575 580 585 Leu Arg Gly Ser Ile ValGly Gly His Glu Pro Gly Glu Pro Arg 590 595 600 Gly Ile Lys Ala Gly TyrGly Thr Cys Asn Cys Phe Pro Glu Glu 605 610 615 Glu Lys Cys Phe Cys GluPro Glu Asp Ile Gln Asp Pro Leu Cys 620 625 630 Asp Glu Leu Cys Arg ThrVal Ile Ala Ala Ala Val Leu Phe Ser 635 640 645 Phe Ile Val Ser Val LeuLeu Ser Ala Phe Cys Ile His Cys Tyr 650 655 660 His Lys Phe Ala His LysPro Pro Ile Ser Ser Ala Glu Met Thr 665 670 675 Phe Arg Arg Pro Ala GlnAla Phe Pro Val Ser Tyr Ser Ser Ser 680 685 690 Gly Ala Arg Arg Pro SerLeu Asp Ser Met Glu Asn Gln Val Ser 695 700 705 Val Asp Ala Phe Lys IleLeu Glu Asp Pro Lys Trp Glu Phe Pro 710 715 720 Arg Lys Asn Leu Val LeuGly Lys Thr Leu Gly Glu Gly Glu Phe 725 730 735 Gly Lys Val Val Lys AlaThr Ala Phe His Leu Lys Gly Arg Ala 740 745 750 Gly Tyr Thr Thr Val AlaVal Lys Met Leu Lys Glu Asn Ala Ser 755 760 765 Pro Ser Glu Leu Arg AspLeu Leu Ser Glu Phe Asn Val Leu Lys 770 775 780 Gln Val Asn His Pro HisVal Ile Lys Leu Tyr Gly Ala Cys Ser 785 790 795 Gln Asp Gly Pro Leu LeuLeu Ile Val Glu Tyr Ala Lys Tyr Gly 800 805 810 Ser Leu Arg Gly Phe LeuArg Glu Ser Arg Lys Val Gly Pro Gly 815 820 825 Tyr Leu Gly Ser Gly GlySer Arg Asn Ser Ser Ser Leu Asp His 830 835 840 Pro Asp Glu Arg Ala LeuThr Met Gly Asp Leu Ile Ser Phe Ala 845 850 855 Trp Gln Ile Ser Gln GlyMet Gln Tyr Leu Ala Glu Met Lys Leu 860 865 870 Val His Arg Asp Leu AlaAla Arg Asn Ile Leu Val Ala Glu Gly 875 880 885 Arg Lys Met Lys Ile SerAsp Phe Gly Leu Ser Arg Asp Val Tyr 890 895 900 Glu Glu Asp Ser Tyr ValLys Arg Ser Gln Gly Arg Ile Pro Val 905 910 915 Lys Trp Met Ala Ile GluSer Leu Phe Asp His Ile Tyr Thr Thr 920 925 930 Gln Ser Asp Val Trp SerPhe Gly Val Leu Leu Trp Glu Ile Val 935 940 945 Thr Leu Gly Gly Asn ProTyr Pro Gly Ile Pro Pro Glu Arg Leu 950 955 960 Phe Asn Leu Leu Lys ThrGly His Arg Met Glu Arg Pro Asp Asn 965 970 975 Cys Ser Glu Glu Met TyrArg Leu Met Leu Gln Cys Trp Lys Gln 980 985 990 Glu Pro Asp Lys Arg ProVal Phe Ala Asp Ile Ser Lys Asp Leu 995 1000 1005 Glu Lys Met Met ValLys Arg Arg Asp Tyr Leu Asp Leu Ala Ala 1010 1015 1020 Ser Thr Pro SerAsp Ser Leu Ile Tyr Asp Asp Gly Leu Ser Glu 1025 1030 1035 Glu Glu ThrPro Leu Val Asp Cys Asn Asn Ala Pro Leu Pro Arg 1040 1045 1050 Ala LeuPro Ser Thr Trp Ile Glu Asn Lys Leu Tyr Gly Met Ser 1055 1060 1065 AspPro Asn Trp Pro Gly Glu Ser Pro Val Pro Leu Thr Arg Ala 1070 1075 1080Asp Gly Thr Asn Thr Gly Phe Pro Arg Tyr Pro Asn Asp Ser Val 1085 10901095 Tyr Ala Asn Trp Met Leu Ser Pro Ser Ala Ala Lys Leu Met Asp 11001105 1110 Thr Phe Asp Ser 75 790 PRT Homo Sapien 75 Met Arg Thr Tyr ArgTyr Phe Leu Leu Leu Phe Trp Val Gly Gln 1 5 10 15 Pro Tyr Pro Thr LeuSer Thr Pro Leu Ser Lys Arg Thr Ser Gly 20 25 30 Phe Pro Ala Lys Lys ArgAla Leu Glu Leu Ser Gly Asn Ser Lys 35 40 45 Asn Glu Leu Asn Arg Ser LysArg Ser Trp Met Trp Asn Gln Phe 50 55 60 Phe Leu Leu Glu Glu Tyr Thr GlySer Asp Tyr Gln Tyr Val Gly 65 70 75 Lys Leu His Ser Asp Gln Asp Arg GlyAsp Gly Ser Leu Lys Tyr 80 85 90 Ile Leu Ser Gly Asp Gly Ala Gly Asp LeuPhe Ile Ile Asn Glu 95 100 105 Asn Thr Gly Asp Ile Gln Ala Thr Lys ArgLeu Asp Arg Glu Glu 110 115 120 Lys Pro Val Tyr Ile Leu Arg Ala Gln AlaIle Asn Arg Arg Thr 125 130 135 Gly Arg Pro Val Glu Pro Glu Ser Glu PheIle Ile Lys Ile His 140 145 150 Asp Ile Asn Asp Asn Glu Pro Ile Phe ThrLys Glu Val Tyr Thr 155 160 165 Ala Thr Val Pro Glu Met Ser Asp Val GlyThr Phe Val Val Gln 170 175 180 Val Thr Ala Thr Asp Ala Asp Asp Pro ThrTyr Gly Asn Ser Ala 185 190 195 Lys Val Val Tyr Ser Ile Leu Gln Gly GlnPro Tyr Phe Ser Val 200 205 210 Glu Ser Glu Thr Gly Ile Ile Lys Thr AlaLeu Leu Asn Met Asp 215 220 225 Arg Glu Asn Arg Glu Gln Tyr Gln Val ValIle Gln Ala Lys Asp 230 235 240 Met Gly Gly Gln Met Gly Gly Leu Ser GlyThr Thr Thr Val Asn 245 250 255 Ile Thr Leu Thr Asp Val Asn Asp Asn ProPro Arg Phe Pro Gln 260 265 270 Ser Thr Tyr Gln Phe Lys Thr Pro Glu SerSer Pro Pro Gly Thr 275 280 285 Pro Ile Gly Arg Ile Lys Ala Ser Asp AlaAsp Val Gly Glu Asn 290 295 300 Ala Glu Ile Glu Tyr Ser Ile Thr Asp GlyGlu Gly Leu Asp Met 305 310 315 Phe Asp Val Ile Thr Asp Gln Glu Thr GlnGlu Gly Ile Ile Thr 320 325 330 Val Lys Lys Leu Leu Asp Phe Glu Lys LysLys Val Tyr Thr Leu 335 340 345 Lys Val Glu Ala Ser Asn Pro Tyr Val GluPro Arg Phe Leu Tyr 350 355 360 Leu Gly Pro Phe Lys Asp Ser Ala Thr ValArg Ile Val Val Glu 365 370 375 Asp Val Asp Glu Pro Pro Val Phe Ser LysLeu Ala Tyr Ile Leu 380 385 390 Gln Ile Arg Glu Asp Ala Gln Ile Asn ThrThr Ile Gly Ser Val 395 400 405 Thr Ala Gln Asp Pro Asp Ala Ala Arg AsnPro Val Lys Tyr Ser 410 415 420 Val Asp Arg His Thr Asp Met Asp Arg IlePhe Asn Ile Asp Ser 425 430 435 Gly Asn Gly Ser Ile Phe Thr Ser Lys LeuLeu Asp Arg Glu Thr 440 445 450 Leu Leu Trp His Asn Ile Thr Val Ile AlaThr Glu Ile Asn Asn 455 460 465 Pro Lys Gln Ser Ser Arg Val Pro Leu TyrIle Lys Val Leu Asp 470 475 480 Val Asn Asp Asn Ala Pro Glu Phe Ala GluPhe Tyr Glu Thr Phe 485 490 495 Val Cys Glu Lys Ala Lys Ala Asp Gln LeuIle Gln Thr Leu His 500 505 510 Ala Val Asp Lys Asp Asp Pro Tyr Ser GlyHis Gln Phe Ser Phe 515 520 525 Ser Leu Ala Pro Glu Ala Ala Ser Gly SerAsn Phe Thr Ile Gln 530 535 540 Asp Asn Lys Asp Asn Thr Ala Gly Ile LeuThr Arg Lys Asn Gly 545 550 555 Tyr Asn Arg His Glu Met Ser Thr Tyr LeuLeu Pro Val Val Ile 560 565 570 Ser Asp Asn Asp Tyr Pro Val Gln Ser SerThr Gly Thr Val Thr 575 580 585 Val Arg Val Cys Ala Cys Asp His His GlyAsn Met Gln Ser Cys 590 595 600 His Ala Glu Ala Leu Ile His Pro Thr GlyLeu Ser Thr Gly Ala 605 610 615 Leu Val Ala Ile Leu Leu Cys Ile Val IleLeu Leu Val Thr Val 620 625 630 Val Leu Phe Ala Ala Leu Arg Arg Gln ArgLys Lys Glu Pro Leu 635 640 645 Ile Ile Ser Lys Glu Asp Ile Arg Asp AsnIle Val Ser Tyr Asn 650 655 660 Asp Glu Gly Gly Gly Glu Glu Asp Thr GlnAla Phe Asp Ile Gly 665 670 675 Thr Leu Arg Asn Pro Glu Ala Ile Glu AspAsn Lys Leu Arg Arg 680 685 690 Asp Ile Val Pro Glu Ala Leu Phe Leu ProArg Arg Thr Pro Thr 695 700 705 Ala Arg Asp Asn Thr Asp Val Arg Asp PheIle Asn Gln Arg Leu 710 715 720 Lys Glu Asn Asp Thr Asp Pro Thr Ala ProPro Tyr Asp Ser Leu 725 730 735 Ala Thr Tyr Ala Tyr Glu Gly Thr Gly SerVal Ala Asp Ser Leu 740 745 750 Ser Ser Leu Glu Ser Val Thr Thr Asp AlaAsp Gln Asp Tyr Asp 755 760 765 Tyr Leu Ser Asp Trp Gly Pro Arg Phe LysLys Leu Ala Asp Met 770 775 780 Tyr Gly Gly Val Asp Ser Asp Lys Asp Ser785 790 76 794 PRT Homo Sapien 76 Met Leu Thr Arg Asn Cys Leu Ser LeuLeu Leu Trp Val Leu Phe 1 5 10 15 Asp Gly Gly Leu Leu Thr Pro Leu GlnPro Gln Pro Gln Gln Thr 20 25 30 Leu Ala Thr Glu Pro Arg Glu Asn Val IleHis Leu Pro Gly Gln 35 40 45 Arg Ser His Phe Gln Arg Val Lys Arg Gly TrpVal Trp Asn Gln 50 55 60 Phe Phe Val Leu Glu Glu Tyr Val Gly Ser Glu ProGln Tyr Val 65 70 75 Gly Lys Leu His Ser Asp Leu Asp Lys Gly Glu Gly ThrVal Lys 80 85 90 Tyr Thr Leu Ser Gly Asp Gly Ala Gly Thr Val Phe Thr IleAsp 95 100 105 Glu Thr Thr Gly Asp Ile His Ala Ile Arg Ser Leu Asp ArgGlu 110 115 120 Glu Lys Pro Phe Tyr Thr Leu Arg Ala Gln Ala Val Asp IleGlu 125 130 135 Thr Arg Lys Pro Leu Glu Pro Glu Ser Glu Phe Ile Ile LysVal 140 145 150 Gln Asp Ile Asn Asp Asn Glu Pro Lys Phe Leu Asp Gly ProTyr 155 160 165 Val Ala Thr Val Pro Glu Met Ser Pro Val Gly Ala Tyr ValLeu 170 175 180 Gln Val Lys Ala Thr Asp Ala Asp Asp Pro Thr Tyr Gly AsnSer 185 190 195 Ala Arg Val Val Tyr Ser Ile Leu Gln Gly Gln Pro Tyr PheSer 200 205 210 Ile Asp Pro Lys Thr Gly Val Ile Arg Thr Ala Leu Pro AsnMet 215 220 225 Asp Arg Glu Val Lys Glu Gln Tyr Gln Val Leu Ile Gln AlaLys 230 235 240 Asp Met Gly Gly Gln Leu Gly Gly Leu Ala Gly Thr Thr IleVal 245 250 255 Asn Ile Thr Leu Thr Asp Val Asn Asp Asn Pro Pro Arg PhePro 260 265 270 Lys Ser Ile Phe His Leu Lys Val Pro Glu Ser Ser Pro IleGly 275 280 285 Ser Ala Ile Gly Arg Ile Arg Ala Val Asp Pro Asp Phe GlyGln 290 295 300 Asn Ala Glu Ile Glu Tyr Asn Ile Val Pro Gly Asp Gly GlyAsn 305 310 315 Leu Phe Asp Ile Val Thr Asp Glu Asp Thr Gln Glu Gly ValIle 320 325 330 Lys Leu Lys Lys Pro Leu Asp Phe Glu Thr Lys Lys Ala TyrThr 335 340 345 Phe Lys Val Glu Ala Ser Asn Leu His Leu Asp His Arg PheHis 350 355 360 Ser Ala Gly Pro Phe Lys Asp Thr Ala Thr Val Lys Ile SerVal 365 370 375 Leu Asp Val Asp Glu Pro Pro Val Phe Ser Lys Pro Leu TyrThr 380 385 390 Met Glu Val Tyr Glu Asp Thr Pro Val Gly Thr Ile Ile GlyAla 395 400 405 Val Thr Ala Gln Asp Leu Asp Val Gly Ser Gly Ala Val ArgTyr 410 415 420 Phe Ile Asp Trp Lys Ser Asp Gly Asp Ser Tyr Phe Thr IleAsp 425 430 435 Gly Asn Glu Gly Thr Ile Ala Thr Asn Glu Leu Leu Asp ArgGlu 440 445 450 Ser Thr Ala Gln Tyr Asn Phe Ser Ile Ile Ala Ser Lys ValSer 455 460 465 Asn Pro Leu Leu Thr Ser Lys Val Asn Ile Leu Ile Asn ValLeu 470 475 480 Asp Val Asn Glu Phe Pro Pro Glu Ile Ser Val Pro Tyr GluThr 485 490 495 Ala Val Cys Glu Asn Ala Lys Pro Gly Gln Ile Ile Gln IleVal 500 505 510 Ser Ala Ala Asp Arg Asp Leu Ser Pro Ala Gly Gln Gln PheSer 515 520 525 Phe Arg Leu Ser Pro Glu Ala Ala Ile Lys Pro Asn Phe ThrVal 530 535 540 Arg Asp Phe Arg Asn Asn Thr Ala Gly Ile Glu Thr Arg ArgAsn 545 550 555 Gly Tyr Ser Arg Arg Gln Gln Glu Leu Tyr Phe Leu Pro ValVal 560 565 570 Ile Glu Asp Ser Ser Tyr Pro Val Gln Ser Ser Thr Asn ThrMet 575 580 585 Thr Ile Arg Val Cys Arg Cys Asp Ser Asp Gly Thr Ile LeuSer 590 595 600 Cys Asn Val Glu Ala Ile Phe Leu Pro Val Gly Leu Ser ThrGly 605 610 615 Ala Leu Ile Ala Ile Leu Leu Cys Ile Val Ile Leu Leu AlaIle 620 625 630 Val Val Leu Tyr Val Ala Leu Arg Arg Gln Lys Lys Lys HisThr 635 640 645 Leu Met Thr Ser Lys Glu Asp Ile Arg Asp Asn Val Ile HisTyr 650 655 660 Asp Asp Glu Gly Gly Gly Glu Glu Asp Thr Gln Ala Phe AspIle 665 670 675 Gly Ala Leu Arg Asn Pro Lys Val Ile Glu Glu Asn Lys IleArg 680 685 690 Arg Asp Ile Lys Pro Asp Ser Leu Cys Leu Pro Arg Gln ArgPro 695 700 705 Pro Met Glu Asp Asn Thr Asp Ile Arg Asp Phe Ile His GlnArg 710 715 720 Leu Gln Glu Asn Asp Val Asp Pro Thr Ala Pro Pro Ile AspSer 725 730 735 Leu Ala Thr Tyr Ala Tyr Glu Gly Ser Gly Ser Val Ala GluSer 740 745 750 Leu Ser Ser Ile Asp Ser Leu Thr Thr Glu Ala Asp Gln AspTyr 755 760 765 Asp Tyr Leu Thr Asp Trp Gly Pro Arg Phe Lys Val Leu AlaAsp 770 775 780 Met Phe Gly Glu Glu Glu Ser Tyr Asn Pro Asp Lys Val Thr785 790 77 141 PRT Homo Sapien 77 Met Ala Arg Pro Leu Cys Thr Leu LeuLeu Leu Met Ala Thr Leu 1 5 10 15 Ala Gly Ala Leu Ala Ser Ser Ser LysGlu Glu Asn Arg Ile Ile 20 25 30 Pro Gly Gly Ile Tyr Asp Ala Asp Leu AsnAsp Glu Trp Val Gln 35 40 45 Arg Ala Leu His Phe Ala Ile Ser Glu Tyr AsnLys Ala Thr Glu 50 55 60 Asp Glu Tyr Tyr Arg Arg Pro Leu Gln Val Leu ArgAla Arg Glu 65 70 75 Gln Thr Phe Gly Gly Val Asn Tyr Phe Phe Asp Val GluVal Gly 80 85 90 Arg Thr Ile Cys Thr Lys Ser Gln Pro Asn Leu Asp Thr CysAla 95 100 105 Phe His Glu Gln Pro Glu Leu Gln Lys Lys Gln Leu Cys SerPhe 110 115 120 Glu Ile Tyr Glu Val Pro Trp Glu Asp Arg Met Ser Leu ValAsn 125 130 135 Ser Arg Cys Gln Glu Ala 140 78 466 PRT Homo Sapien 78Met Thr Thr Ser Pro Ile Leu Gln Leu Leu Leu Arg Leu Ser Leu 1 5 10 15Cys Gly Leu Leu Leu Gln Arg Ala Glu Thr Gly Ser Lys Gly Gln 20 25 30 ThrAla Gly Glu Leu Tyr Gln Arg Trp Glu Arg Tyr Arg Arg Glu 35 40 45 Cys GlnGlu Thr Leu Ala Ala Ala Glu Pro Pro Ser Gly Leu Ala 50 55 60 Cys Asn GlySer Phe Asp Met Tyr Val Cys Trp Asp Tyr Ala Ala 65 70 75 Pro Asn Ala ThrAla Arg Ala Ser Cys Pro Trp Tyr Leu Pro Trp 80 85 90 His His His Val AlaAla Gly Phe Val Leu Arg Gln Cys Gly Ser 95 100 105 Asp Gly Gln Trp GlyLeu Trp Arg Asp His Thr Gln Cys Glu Asn 110 115 120 Pro Glu Lys Asn GluAla Phe Leu Asp Gln Arg Leu Ile Leu Glu 125 130 135 Arg Leu Gln Val MetTyr Thr Val Gly Tyr Ser Leu Ser Leu Ala 140 145 150 Thr Leu Leu Leu AlaLeu Leu Ile Leu Ser Leu Phe Arg Arg Leu 155 160 165 His Cys Thr Arg AsnTyr Ile His Ile Asn Leu Phe Thr Ser Phe 170 175 180 Met Leu Arg Ala AlaAla Ile Leu Ser Arg Asp Arg Leu Leu Pro 185 190 195 Arg Pro Gly Pro TyrLeu Gly Asp Gln Ala Leu Ala Leu Trp Asn 200 205 210 Gln Ala Leu Ala AlaCys Arg Thr Ala Gln Ile Val Thr Gln Tyr 215 220 225 Cys Val Gly Ala AsnTyr Thr Trp Leu Leu Val Glu Gly Val Tyr 230 235 240 Leu His Ser Leu LeuVal Leu Val Gly Gly Ser Glu Glu Gly His 245 250 255 Phe Arg Tyr Tyr LeuLeu Leu Gly Trp Gly Ala Pro Ala Leu Phe 260 265 270 Val Ile Pro Trp ValIle Val Arg Tyr Leu Tyr Glu Asn Thr Gln 275 280 285 Cys Trp Glu Arg AsnGlu Val Lys Ala Ile Trp Trp Ile Ile Arg 290 295 300 Thr Pro Ile Leu MetThr Ile Leu Ile Asn Phe Leu Ile Phe Ile 305 310 315 Arg Ile Leu Gly IleLeu Leu Ser Lys Leu Arg Thr Arg Gln Met 320 325 330 Arg Cys Arg Asp TyrArg Leu Arg Leu Ala Arg Ser Thr Leu Thr 335 340 345 Leu Val Pro Leu LeuGly Val His Glu Val Val Phe Ala Pro Val 350 355 360 Thr Glu Glu Gln AlaArg Gly Ala Leu Arg Phe Ala Lys Leu Gly 365 370 375 Phe Glu Ile Phe LeuSer Ser Phe Gln Gly Phe Leu Val Ser Val 380 385 390 Leu Tyr Cys Phe IleAsn Lys Glu Val Gln Ser Glu Ile Arg Arg 395 400 405 Gly Trp His His CysArg Leu Arg Arg Ser Leu Gly Glu Glu Gln 410 415 420 Arg Gln Leu Pro GluArg Ala Phe Arg Ala Leu Pro Ser Gly Ser 425 430 435 Gly Pro Gly Glu ValPro Thr Ser Arg Gly Leu Ser Ser Gly Thr 440 445 450 Leu Pro Gly Pro GlyAsn Glu Ala Ser Arg Glu Leu Glu Ser Tyr 455 460 465 Cys 79 506 PRT HomoSapien 79 Met Leu Ser Lys Val Leu Pro Val Leu Leu Gly Ile Leu Leu Ile 15 10 15 Leu Gln Ser Arg Val Glu Gly Pro Gln Thr Glu Ser Lys Asn Glu 2025 30 Ala Ser Ser Arg Asp Val Val Tyr Gly Pro Gln Pro Gln Pro Leu 35 4045 Glu Asn Gln Leu Leu Ser Glu Glu Thr Lys Ser Thr Glu Thr Glu 50 55 60Thr Gly Ser Arg Val Gly Lys Leu Pro Glu Ala Ser Arg Ile Leu 65 70 75 AsnThr Ile Leu Ser Asn Tyr Asp His Lys Leu Arg Pro Gly Ile 80 85 90 Gly GluLys Pro Thr Val Val Thr Val Glu Ile Ala Val Asn Ser 95 100 105 Leu GlyPro Leu Ser Ile Leu Asp Met Glu Tyr Thr Ile Asp Ile 110 115 120 Ile PheSer Gln Thr Trp Tyr Asp Glu Arg Leu Cys Tyr Asn Asp 125 130 135 Thr PheGlu Ser Leu Val Leu Asn Gly Asn Val Val Ser Gln Leu 140 145 150 Trp IlePro Asp Thr Phe Phe Arg Asn Ser Lys Arg Thr His Glu 155 160 165 His GluIle Thr Met Pro Asn Gln Met Val Arg Ile Tyr Lys Asp 170 175 180 Gly LysVal Leu Tyr Thr Ile Arg Met Thr Ile Asp Ala Gly Cys 185 190 195 Ser LeuHis Met Leu Arg Phe Pro Met Asp Ser His Ser Cys Pro 200 205 210 Leu SerPhe Ser Ser Phe Ser Tyr Pro Glu Asn Glu Met Ile Tyr 215 220 225 Lys TrpGlu Asn Phe Lys Leu Glu Ile Asn Glu Lys Asn Ser Trp 230 235 240 Lys LeuPhe Gln Phe Asp Phe Thr Gly Val Ser Asn Lys Thr Glu 245 250 255 Ile IleThr Thr Pro Val Gly Asp Phe Met Val Met Thr Ile Phe 260 265 270 Phe AsnVal Ser Arg Arg Phe Gly Tyr Val Ala Phe Gln Asn Tyr 275 280 285 Val ProSer Ser Val Thr Thr Met Leu Ser Trp Val Ser Phe Trp 290 295 300 Ile LysThr Glu Ser Ala Pro Ala Arg Thr Ser Leu Gly Ile Thr 305 310 315 Ser ValLeu Thr Met Thr Thr Leu Gly Thr Phe Ser Arg Lys Asn 320 325 330 Phe ProArg Val Ser Tyr Ile Thr Ala Leu Asp Phe Tyr Ile Ala 335 340 345 Ile CysPhe Val Phe Cys Phe Cys Ala Leu Leu Glu Phe Ala Val 350 355 360 Leu AsnPhe Leu Ile Tyr Asn Gln Thr Lys Ala His Ala Ser Pro 365 370 375 Lys LeuArg His Pro Arg Ile Asn Ser Arg Ala His Ala Arg Thr 380 385 390 Arg AlaArg Ser Arg Ala Cys Ala Arg Gln His Gln Glu Ala Phe 395 400 405 Val CysGln Ile Val Thr Thr Glu Gly Ser Asp Gly Glu Glu Arg 410 415 420 Pro SerCys Ser Ala Gln Gln Pro Pro Ser Pro Gly Ser Pro Glu 425 430 435 Gly ProArg Ser Leu Cys Ser Lys Leu Ala Cys Cys Glu Trp Cys 440 445 450 Lys ArgPhe Lys Lys Tyr Phe Cys Met Val Pro Asp Cys Glu Gly 455 460 465 Ser ThrTrp Gln Gln Gly Arg Leu Cys Ile His Val Tyr Arg Leu 470 475 480 Asp AsnTyr Ser Arg Val Val Phe Pro Val Thr Phe Phe Phe Phe 485 490 495 Asn ValLeu Tyr Trp Leu Val Cys Leu Asn Leu 500 505 80 1212 PRT Homo Sapien 80Met Glu Pro Arg Pro Thr Ala Pro Ser Ser Gly Ala Pro Gly Leu 1 5 10 15Ala Gly Val Gly Glu Thr Pro Ser Ala Ala Ala Leu Ala Ala Ala 20 25 30 ArgVal Glu Leu Pro Gly Thr Ala Val Pro Ser Val Pro Glu Asp 35 40 45 Ala AlaPro Ala Ser Arg Asp Gly Gly Gly Val Arg Asp Glu Gly 50 55 60 Pro Ala AlaAla Gly Asp Gly Leu Gly Arg Pro Leu Gly Pro Thr 65 70 75 Pro Ser Gln SerArg Phe Gln Val Asp Leu Val Ser Glu Asn Ala 80 85 90 Gly Arg Ala Ala AlaAla Ala Ala Ala Ala Ala Ala Ala Ala Ala 95 100 105 Ala Ala Gly Ala GlyAla Gly Ala Lys Gln Thr Pro Ala Asp Gly 110 115 120 Glu Ala Ser Gly GluSer Glu Pro Ala Lys Gly Ser Glu Glu Ala 125 130 135 Lys Gly Arg Phe ArgVal Asn Phe Val Asp Pro Ala Ala Ser Ser 140 145 150 Ser Ala Glu Asp SerLeu Ser Asp Ala Ala Gly Val Gly Val Asp 155 160 165 Gly Pro Asn Val SerPhe Gln Asn Gly Gly Asp Thr Val Leu Ser 170 175 180 Glu Gly Ser Ser LeuHis Ser Gly Gly Gly Gly Gly Ser Gly His 185 190 195 His Gln His Tyr TyrTyr Asp Thr His Thr Asn Thr Tyr Tyr Leu 200 205 210 Arg Thr Phe Gly HisAsn Thr Met Asp Ala Val Pro Arg Ile Asp 215 220 225 His Tyr Arg His ThrAla Ala Gln Leu Gly Glu Lys Leu Leu Arg 230 235 240 Pro Ser Leu Ala GluLeu His Asp Glu Leu Glu Lys Glu Pro Phe 245 250 255 Glu Asp Gly Phe AlaAsn Gly Glu Glu Ser Thr Pro Thr Arg Asp 260 265 270 Ala Val Val Thr TyrThr Ala Glu Ser Lys Gly Val Val Lys Phe 275 280 285 Gly Trp Ile Lys GlyVal Leu Val Arg Cys Met Leu Asn Ile Trp 290 295 300 Gly Val Met Leu PheIle Arg Leu Ser Trp Ile Val Gly Gln Ala 305 310 315 Gly Ile Gly Leu SerVal Leu Val Ile Met Met Ala Thr Val Val 320 325 330 Thr Thr Ile Thr GlyLeu Ser Thr Ser Ala Ile Ala Thr Asn Gly 335 340 345 Phe Val Arg Gly GlyGly Ala Tyr Tyr Leu Ile Ser Arg Ser Leu 350 355 360 Gly Pro Glu Phe GlyGly Ala Ile Gly Leu Ile Phe Ala Phe Ala 365 370 375 Asn Ala Val Ala ValAla Met Tyr Val Val Gly Phe Ala Glu Thr 380 385 390 Val Val Glu Leu LeuLys Glu His Ser Ile Leu Met Ile Asp Glu 395 400 405 Ile Asn Asp Ile ArgIle Ile Gly Ala Ile Thr Val Val Ile Leu 410 415 420 Leu Gly Ile Ser ValAla Gly Met Glu Trp Glu Ala Lys Ala Gln 425 430 435 Ile Val Leu Leu ValIle Leu Leu Leu Ala Ile Gly Asp Phe Val 440 445 450 Ile Gly Thr Phe IlePro Leu Glu Ser Lys Lys Pro Lys Gly Phe 455 460 465 Phe Gly Tyr Lys SerGlu Ile Phe Asn Glu Asn Phe Gly Pro Asp 470 475 480 Phe Arg Glu Glu GluThr Phe Phe Ser Val Phe Ala Ile Phe Phe 485 490 495 Pro Ala Ala Thr GlyIle Leu Ala Gly Ala Asn Ile Ser Gly Asp 500 505 510 Leu Ala Asp Pro GlnSer Ala Ile Pro Lys Gly Thr Leu Leu Ala 515 520 525 Ile Leu Ile Thr ThrLeu Val Tyr Val Gly Ile Ala Val Ser Val 530 535 540 Gly Ser Cys Val ValArg Asp Ala Thr Gly Asn Val Asn Asp Thr 545 550 555 Ile Val Thr Glu LeuThr Asn Cys Thr Ser Ala Ala Cys Lys Leu 560 565 570 Asn Phe Asp Phe SerSer Cys Glu Ser Ser Pro Cys Ser Tyr Gly 575 580 585 Leu Met Asn Asn PheGln Val Met Ser Met Val Ser Gly Phe Thr 590 595 600 Pro Leu Ile Ser AlaGly Ile Phe Ser Ala Thr Leu Ser Ser Ala 605 610 615 Leu Ala Ser Leu ValSer Ala Pro Lys Ile Phe Gln Ala Leu Cys 620 625 630 Lys Asp Asn Ile TyrPro Ala Phe Gln Met Phe Ala Lys Gly Tyr 635 640 645 Gly Lys Asn Asn GluPro Leu Arg Gly Tyr Ile Leu Thr Phe Leu 650 655 660 Ile Ala Leu Gly PheIle Leu Ile Ala Glu Leu Asn Val Ile Ala 665 670 675 Pro Ile Ile Ser AsnPhe Phe Leu Ala Ser Tyr Ala Leu Ile Asn 680 685 690 Phe Ser Val Phe HisAla Ser Leu Ala Lys Ser Pro Gly Trp Arg 695 700 705 Pro Ala Phe Lys TyrTyr Asn Met Trp Ile Ser Leu Leu Gly Ala 710 715 720 Ile Leu Cys Cys IleVal Met Phe Val Ile Asn Trp Trp Ala Ala 725 730 735 Leu Leu Thr Tyr ValIle Val Leu Gly Leu Tyr Ile Tyr Val Thr 740 745 750 Tyr Lys Lys Pro AspVal Asn Trp Gly Ser Ser Thr Gln Ala Leu 755 760 765 Thr Tyr Leu Asn AlaLeu Gln His Ser Ile Arg Leu Ser Gly Val 770 775 780 Glu Asp His Val LysAsn Phe Arg Pro Gln Cys Leu Val Met Thr 785 790 795 Gly Ala Pro Asn SerArg Pro Ala Leu Leu His Leu Val His Asp 800 805 810 Phe Thr Lys Asn ValGly Leu Met Ile Cys Gly His Val His Met 815 820 825 Gly Pro Arg Arg GlnAla Met Lys Glu Met Ser Ile Asp Gln Ala 830 835 840 Lys Tyr Gln Arg TrpLeu Ile Lys Asn Lys Met Lys Ala Phe Tyr 845 850 855 Ala Pro Val His AlaAsp Asp Leu Arg Glu Gly Ala Gln Tyr Leu 860 865 870 Met Gln Ala Ala GlyLeu Gly Arg Met Lys Pro Asn Thr Leu Val 875 880 885 Leu Gly Phe Lys LysAsp Trp Leu Gln Ala Asp Met Arg Asp Val 890 895 900 Asp Met Tyr Ile AsnLeu Phe His Asp Ala Phe Asp Ile Gln Tyr 905 910 915 Gly Val Val Val IleArg Leu Lys Glu Gly Leu Asp Ile Ser His 920 925 930 Leu Gln Gly Gln GluGlu Leu Leu Ser Ser Gln Glu Lys Ser Pro 935 940 945 Gly Thr Lys Asp ValVal Val Ser Val Glu Tyr Ser Lys Lys Ser 950 955 960 Asp Leu Asp Thr SerLys Pro Leu Ser Glu Lys Pro Ile Thr His 965 970 975 Lys Val Glu Glu GluAsp Gly Lys Thr Ala Thr Gln Pro Leu Leu 980 985 990 Lys Lys Glu Ser LysGly Pro Ile Val Pro Leu Asn Val Ala Asp 995 1000 1005 Gln Lys Leu LeuGlu Ala Ser Thr Gln Phe Gln Lys Lys Gln Gly 1010 1015 1020 Lys Asn ThrIle Asp Val Trp Trp Leu Phe Asp Asp Gly Gly Leu 1025 1030 1035 Thr LeuLeu Ile Pro Tyr Leu Leu Thr Thr Lys Lys Lys Trp Lys 1040 1045 1050 AspCys Lys Ile Arg Val Phe Ile Gly Gly Lys Ile Asn Arg Ile 1055 1060 1065Asp His Asp Arg Arg Ala Met Ala Thr Leu Leu Ser Lys Phe Arg 1070 10751080 Ile Asp Phe Ser Asp Ile Met Val Leu Gly Asp Ile Asn Thr Lys 10851090 1095 Pro Lys Lys Glu Asn Ile Ile Ala Phe Glu Glu Ile Ile Glu Pro1100 1105 1110 Tyr Arg Leu His Glu Asp Asp Lys Glu Gln Asp Ile Ala AspLys 1115 1120 1125 Met Lys Glu Asp Glu Pro Trp Arg Ile Thr Asp Asn GluLeu Glu 1130 1135 1140 Leu Tyr Lys Thr Lys Thr Tyr Arg Gln Ile Arg LeuAsn Glu Leu 1145 1150 1155 Leu Lys Glu His Ser Ser Thr Ala Asn Ile IleVal Met Ser Leu 1160 1165 1170 Pro Val Ala Arg Lys Gly Ala Val Ser SerAla Leu Tyr Met Ala 1175 1180 1185 Trp Leu Glu Ala Leu Ser Lys Asp LeuPro Pro Ile Leu Leu Val 1190 1195 1200 Arg Gly Asn His Gln Ser Val LeuThr Phe Tyr Ser 1205 1210 81 674 PRT Homo Sapien 81 Met Ala Thr Ala ValSer Arg Pro Cys Ala Gly Arg Ser Arg Asp 1 5 10 15 Ile Leu Trp Arg ValLeu Gly Trp Arg Ile Val Ala Ser Ile Val 20 25 30 Trp Ser Val Leu Phe LeuPro Ile Cys Thr Thr Val Phe Ile Ile 35 40 45 Phe Ser Arg Ile Asp Leu PheHis Pro Ile Gln Trp Leu Ser Asp 50 55 60 Ser Phe Ser Asp Leu Tyr Ser SerTyr Val Ile Phe Tyr Phe Leu 65 70 75 Leu Leu Ser Val Val Ile Ile Ile IleSer Ile Phe Asn Val Glu 80 85 90 Phe Tyr Ala Val Val Pro Ser Ile Pro CysSer Arg Leu Ala Leu 95 100 105 Ile Gly Lys Ile Ile His Pro Gln Gln LeuMet His Ser Phe Ile 110 115 120 His Ala Ala Met Gly Met Val Met Ala TrpCys Ala Ala Val Ile 125 130 135 Thr Gln Gly Gln Tyr Ser Phe Leu Val ValPro Cys Thr Gly Thr 140 145 150 Asn Ser Phe Gly Ser Pro Ala Ala Gln ThrCys Leu Asn Glu Tyr 155 160 165 His Leu Phe Phe Leu Leu Thr Gly Ala PheMet Gly Tyr Ser Tyr 170 175 180 Ser Leu Leu Tyr Phe Val Asn Asn Met AsnTyr Leu Pro Phe Pro 185 190 195 Ile Ile Gln Gln Tyr Lys Phe Leu Arg PheArg Arg Ser Leu Leu 200 205 210 Leu Leu Val Lys His Ser Cys Val Glu SerLeu Phe Leu Val Arg 215 220 225 Asn Phe Cys Ile Leu Tyr Tyr Phe Leu GlyTyr Ile Pro Lys Ala 230 235 240 Trp Ile Ser Thr Ala Met Asn Leu His IleAsp Glu Gln Val His 245 250 255 Arg Pro Leu Asp Thr Val Ser Gly Leu LeuAsn Leu Ser Leu Leu 260 265 270 Tyr His Val Trp Leu Cys Gly Val Phe LeuLeu Thr Thr Trp Tyr 275 280 285 Val Ser Trp Ile Leu Phe Lys Ile Tyr AlaThr Glu Ala His Val 290 295 300 Phe Pro Val Gln Pro Pro Phe Ala Glu GlySer Asp Glu Cys Leu 305 310 315 Pro Lys Val Leu Asn Ser Asn Pro Pro ProIle Ile Lys Tyr Leu 320 325 330 Ala Leu Gln Asp Leu Met Leu Leu Ser GlnTyr Ser Pro Ser Arg 335 340 345 Arg Gln Glu Val Phe Ser Leu Ser Gln ProGly Gly His Pro His 350 355 360 Asn Trp Thr Ala Ile Ser Arg Glu Cys LeuAsn Leu Leu Asn Gly 365 370 375 Met Thr Gln Lys Leu Ile Leu Tyr Gln GluAla Ala Ala Thr Asn 380 385 390 Gly Arg Val Ser Ser Ser Tyr Pro Val GluPro Lys Lys Leu Asn 395 400 405 Ser Pro Glu Glu Thr Ala Phe Gln Thr ProLys Ser Ser Gln Met 410 415 420 Pro Arg Pro Ser Val Pro Pro Leu Val LysThr Ser Leu Phe Ser 425 430 435 Ser Lys Leu Ser Thr Pro Asp Val Val SerPro Phe Gly Thr Pro 440 445 450 Phe Gly Ser Ser Val Met Asn Arg Met AlaGly Ile Phe Asp Val 455 460 465 Asn Thr Cys Tyr Gly Ser Pro Gln Ser ProGln Leu Ile Arg Arg 470 475 480 Gly Pro Arg Leu Trp Thr Ser Ala Ser AspGln Gln Met Thr Glu 485 490 495 Phe Ser Asn Pro Ser Pro Ser Thr Ser IleSer Ala Glu Gly Lys 500 505 510 Thr Met Arg Gln Pro Ser Val Ile Tyr SerTrp Ile Gln Asn Lys 515 520 525 Arg Glu Gln Ile Lys Asn Phe Leu Ser LysArg Val Leu Ile Met 530 535 540 Tyr Phe Phe Ser Lys His Pro Glu Ala SerIle Gln Ala Val Phe 545 550 555 Ser Asp Ala Gln Met His Ile Trp Ala LeuGlu Gly Leu Ser His 560 565 570 Leu Val Ala Ala Ser Phe Thr Glu Asp ArgPhe Gly Val Val Gln 575 580 585 Thr Thr Leu Pro Ala Ile Leu Asn Thr LeuLeu Thr Leu Gln Glu 590 595 600 Ala Val Asp Lys Tyr Phe Lys Leu Pro HisAla Ser Ser Lys Pro 605 610 615 Pro Arg Ile Ser Gly Ser Leu Val Asp ThrSer Tyr Lys Thr Leu 620 625 630 Arg Phe Ala Phe Arg Ala Ser Leu Lys ThrAla Ile Tyr Arg Ile 635 640 645 Thr Thr Thr Phe Gly Glu His Leu Asn AlaVal Gln Ala Ser Ala 650 655 660 Glu His Gln Lys Arg Leu Gln Gln Phe LeuGlu Phe Lys Glu 665 670 82 1321 PRT Homo Sapien 82 Met Gly Ala Pro PheVal Trp Ala Leu Gly Leu Leu Met Leu Gln 1 5 10 15 Met Leu Leu Phe ValAla Gly Glu Gln Gly Thr Gln Asp Ile Thr 20 25 30 Asp Ala Ser Glu Arg GlyLeu His Met Gln Lys Leu Gly Ser Gly 35 40 45 Ser Val Gln Ala Ala Leu AlaGlu Leu Val Ala Leu Pro Cys Leu 50 55 60 Phe Thr Leu Gln Pro Arg Pro SerAla Ala Arg Asp Ala Pro Arg 65 70 75 Ile Lys Trp Thr Lys Val Arg Thr AlaSer Gly Gln Arg Gln Asp 80 85 90 Leu Pro Ile Leu Val Ala Lys Asp Asn ValVal Arg Val Ala Lys 95 100 105 Ser Trp Gln Gly Arg Val Ser Leu Pro SerTyr Pro Arg Arg Arg 110 115 120 Ala Asn Ala Thr Leu Leu Leu Gly Pro LeuArg Ala Ser Asp Ser 125 130 135 Gly Leu Tyr Arg Cys Gln Val Val Arg GlyIle Glu Asp Glu Gln 140 145 150 Asp Leu Val Pro Leu Glu Val Thr Gly ValVal Phe His Tyr Arg 155 160 165 Ser Ala Arg Asp Arg Tyr Ala Leu Thr PheAla Glu Ala Gln Glu 170 175 180 Ala Cys Arg Leu Ser Ser Ala Ile Ile AlaAla Pro Arg His Leu 185 190 195 Gln Ala Ala Phe Glu Asp Gly Phe Asp AsnCys Asp Ala Gly Trp 200 205 210 Leu Ser Asp Arg Thr Val Arg Tyr Pro IleThr Gln Ser Arg Pro 215 220 225 Gly Cys Tyr Gly Asp Arg Ser Ser Leu ProGly Val Arg Ser Tyr 230 235 240 Gly Arg Arg Asn Pro Gln Glu Leu Tyr AspVal Tyr Cys Phe Ala 245 250 255 Arg Glu Leu Gly Gly Glu Val Phe Tyr ValGly Pro Ala Arg Arg 260 265 270 Leu Thr Leu Ala Gly Ala Arg Ala Gln CysArg Arg Gln Gly Ala 275 280 285 Ala Leu Ala Ser Val Gly Gln Leu His LeuAla Trp His Glu Gly 290 295 300 Leu Asp Gln Cys Asp Pro Gly Trp Leu AlaAsp Gly Ser Val Arg 305 310 315 Tyr Pro Ile Gln Thr Pro Arg Arg Arg CysGly Gly Pro Ala Pro 320 325 330 Gly Val Arg Thr Val Tyr Arg Phe Ala AsnArg Thr Gly Phe Pro 335 340 345 Ser Pro Ala Glu Arg Phe Asp Ala Tyr CysPhe Arg Ala His His 350 355 360 Pro Thr Ser Gln His Gly Asp Leu Glu ThrPro Ser Ser Gly Asp 365 370 375 Glu Gly Glu Ile Leu Ser Ala Glu Gly ProPro Val Arg Glu Leu 380 385 390 Glu Pro Thr Leu Glu Glu Glu Glu Val ValThr Pro Asp Phe Gln 395 400 405 Glu Pro Leu Val Ser Ser Gly Glu Glu GluThr Leu Ile Leu Glu 410 415 420 Glu Lys Gln Glu Ser Gln Gln Thr Leu SerPro Thr Pro Gly Asp 425 430 435 Pro Met Leu Ala Ser Trp Pro Thr Gly GluVal Trp Leu Ser Thr 440 445 450 Val Ala Pro Ser Pro Ser Asp Met Gly AlaGly Thr Ala Ala Ser 455 460 465 Ser His Thr Glu Val Ala Pro Thr Asp ProMet Pro Arg Arg Arg 470 475 480 Gly Arg Phe Lys Gly Leu Asn Gly Arg TyrPhe Gln Gln Gln Glu 485 490 495 Pro Glu Pro Gly Leu Gln Gly Gly Met GluAla Ser Ala Gln Pro 500 505 510 Pro Thr Ser Glu Ala Ala Val Asn Gln MetGlu Pro Pro Leu Ala 515 520 525 Met Ala Val Thr Glu Met Leu Gly Ser GlyGln Ser Arg Ser Pro 530 535 540 Trp Ala Asp Leu Thr Asn Glu Val Asp MetPro Gly Ala Gly Ser 545 550 555 Ala Gly Gly Lys Ser Ser Pro Glu Pro TrpLeu Trp Pro Pro Thr 560 565 570 Met Val Pro Pro Ser Ile Ser Gly His SerArg Ala Pro Val Leu 575 580 585 Glu Leu Glu Lys Ala Glu Gly Pro Ser AlaArg Pro Ala Thr Pro 590 595 600 Asp Leu Phe Trp Ser Pro Leu Glu Ala ThrVal Ser Ala Pro Ser 605 610 615 Pro Ala Pro Trp Glu Ala Phe Pro Val AlaThr Ser Pro Asp Leu 620 625 630 Pro Met Met Ala Met Leu Arg Gly Pro LysGlu Trp Met Leu Pro 635 640 645 His Pro Thr Pro Ile Ser Thr Glu Ala AsnArg Val Glu Ala His 650 655 660 Gly Glu Ala Thr Ala Thr Ala Pro Pro SerPro Ala Ala Glu Thr 665 670 675 Lys Val Tyr Ser Leu Pro Leu Ser Leu ThrPro Thr Gly Gln Gly 680 685 690 Gly Glu Ala Met Pro Thr Thr Pro Glu SerPro Arg Ala Asp Phe 695 700 705 Arg Glu Thr Gly Glu Thr Ser Pro Ala GlnVal Asn Lys Ala Glu 710 715 720 His Ser Ser Ser Ser Pro Trp Pro Ser ValAsn Arg Asn Val Ala 725 730 735 Val Gly Phe Val Pro Thr Glu Thr Ala ThrGlu Pro Thr Gly Leu 740 745 750 Arg Gly Ile Pro Gly Ser Glu Ser Gly ValPhe Asp Thr Ala Glu 755 760 765 Ser Pro Thr Ser Gly Leu Gln Ala Thr ValAsp Glu Val Gln Asp 770 775 780 Pro Trp Pro Ser Val Tyr Ser Lys Gly LeuAsp Ala Ser Ser Pro 785 790 795 Ser Ala Pro Leu Gly Ser Pro Gly Val PheLeu Val Pro Lys Val 800 805 810 Thr Pro Asn Leu Glu Pro Trp Val Ala ThrAsp Glu Gly Pro Thr 815 820 825 Val Asn Pro Met Asp Ser Thr Val Thr ProAla Pro Ser Asp Ala 830 835 840 Ser Gly Ile Trp Glu Pro Gly Ser Gln ValPhe Glu Glu Ala Glu 845 850 855 Ser Thr Thr Leu Ser Pro Gln Val Ala LeuAsp Thr Ser Ile Val 860 865 870 Thr Pro Leu Thr Thr Leu Glu Gln Gly AspLys Val Gly Val Pro 875 880 885 Ala Met Ser Thr Leu Gly Ser Ser Ser SerGln Pro His Pro Glu 890 895 900 Pro Glu Asp Gln Val Glu Thr Gln Gly ThrSer Gly Ala Ser Val 905 910 915 Pro Pro His Gln Ser Ser Pro Leu Gly LysPro Ala Val Pro Pro 920 925 930 Gly Thr Pro Thr Ala Ala Ser Val Gly GluSer Ala Ser Val Ser 935 940 945 Ser Gly Glu Pro Thr Val Pro Trp Asp ProSer Ser Thr Leu Leu 950 955 960 Pro Val Thr Leu Gly Ile Glu Asp Phe GluLeu Glu Val Leu Ala 965 970 975 Gly Ser Pro Gly Val Glu Ser Phe Trp GluGlu Val Ala Ser Gly 980 985 990 Glu Glu Pro Ala Leu Pro Gly Thr Pro MetAsn Ala Gly Ala Glu 995 1000 1005 Glu Val His Ser Asp Pro Cys Glu AsnAsn Pro Cys Leu His Gly 1010 1015 1020 Gly Thr Cys Asn Ala Asn Gly ThrMet Tyr Gly Cys Ser Cys Asp 1025 1030 1035 Gln Gly Phe Ala Gly Glu AsnCys Glu Ile Asp Ile Asp Asp Cys 1040 1045 1050 Leu Cys Ser Pro Cys GluAsn Gly Gly Thr Cys Ile Asp Glu Val 1055 1060 1065 Asn Gly Phe Val CysLeu Cys Leu Pro Ser Tyr Gly Gly Ser Phe 1070 1075 1080 Cys Glu Lys AspThr Glu Gly Cys Asp Arg Gly Trp His Lys Phe 1085 1090 1095 Gln Gly HisCys Tyr Arg Tyr Phe Ala His Arg Arg Ala Trp Glu 1100 1105 1110 Asp AlaGlu Lys Asp Cys Arg Arg Arg Ser Gly His Leu Thr Ser 1115 1120 1125 ValHis Ser Pro Glu Glu His Ser Phe Ile Asn Ser Phe Gly His 1130 1135 1140Glu Asn Thr Trp Ile Gly Leu Asn Asp Arg Ile Val Glu Arg Asp 1145 11501155 Phe Gln Trp Thr Asp Asn Thr Gly Leu Gln Phe Glu Asn Trp Arg 11601165 1170 Glu Asn Gln Pro Asp Asn Phe Phe Ala Gly Gly Glu Asp Cys Val1175 1180 1185 Val Met Val Ala His Glu Ser Gly Arg Trp Asn Asp Val ProCys 1190 1195 1200 Asn Tyr Asn Leu Pro Tyr Val Cys Lys Lys Gly Thr ValLeu Cys 1205 1210 1215 Gly Pro Pro Pro Ala Val Glu Asn Ala Ser Leu IleGly Ala Arg 1220 1225 1230 Lys Ala Lys Asn Asn Val His Ala Thr Val ArgTyr Gln Cys Asn 1235 1240 1245 Glu Gly Phe Ala Gln His His Val Val ThrIle Arg Cys Arg Ser 1250 1255 1260 Asn Gly Lys Trp Asp Arg Pro Gln IleVal Cys Thr Lys Pro Arg 1265 1270 1275 Arg Ser His Arg Met Arg Gly HisHis His His His Gln His His 1280 1285 1290 His Gln His His His His LysSer Arg Lys Glu Arg Arg Lys His 1295 1300 1305 Lys Lys His Pro Thr GluAsp Trp Glu Lys Asp Glu Gly Asn Phe 1310 1315 1320 Cys 83 696 PRT HomoSapien 83 Met Lys Phe Ala Glu His Leu Ser Ala His Ile Thr Pro Glu Trp 15 10 15 Arg Lys Gln Tyr Ile Gln Tyr Glu Ala Phe Lys Asp Met Leu Tyr 2025 30 Ser Ala Gln Asp Gln Ala Pro Ser Val Glu Val Thr Asp Glu Asp 35 4045 Thr Val Lys Arg Tyr Phe Ala Lys Phe Glu Glu Lys Phe Phe Gln 50 55 60Thr Cys Glu Lys Glu Leu Ala Lys Ile Asn Thr Phe Tyr Ser Glu 65 70 75 LysLeu Ala Glu Ala Gln Arg Arg Phe Ala Thr Leu Gln Asn Glu 80 85 90 Leu GlnSer Ser Leu Asp Ala Gln Lys Glu Ser Thr Gly Val Thr 95 100 105 Thr LeuArg Gln Arg Arg Lys Pro Val Phe His Leu Ser His Glu 110 115 120 Glu ArgVal Gln His Arg Asn Ile Lys Asp Leu Lys Leu Ala Phe 125 130 135 Ser GluPhe Tyr Leu Ser Leu Ile Leu Leu Gln Asn Tyr Gln Asn 140 145 150 Leu AsnPhe Thr Gly Phe Arg Lys Ile Leu Lys Lys His Asp Lys 155 160 165 Ile LeuGlu Thr Ser Arg Gly Ala Asp Trp Arg Val Ala His Val 170 175 180 Glu ValAla Pro Phe Tyr Thr Cys Lys Lys Ile Asn Gln Leu Ile 185 190 195 Ser GluThr Glu Ala Val Val Thr Asn Glu Leu Glu Asp Gly Asp 200 205 210 Arg GlnLys Ala Met Lys Arg Leu Arg Val Pro Pro Leu Gly Ala 215 220 225 Ala GlnPro Ala Pro Ala Trp Thr Thr Phe Arg Val Gly Leu Phe 230 235 240 Cys GlyIle Phe Ile Val Leu Asn Ile Thr Leu Val Leu Ala Ala 245 250 255 Val PheLys Leu Glu Thr Asp Arg Ser Ile Trp Pro Leu Ile Arg 260 265 270 Ile TyrArg Gly Gly Phe Leu Leu Ile Glu Phe Leu Phe Leu Leu 275 280 285 Gly IleAsn Thr Tyr Gly Trp Arg Gln Ala Gly Val Asn His Val 290 295 300 Leu IlePhe Glu Leu Asn Pro Arg Ser Asn Leu Ser His Gln His 305 310 315 Leu PheGlu Ile Ala Gly Phe Leu Gly Ile Leu Trp Cys Leu Ser 320 325 330 Leu LeuAla Cys Phe Phe Ala Pro Ile Ser Val Ile Pro Thr Tyr 335 340 345 Val TyrPro Leu Ala Leu Tyr Gly Phe Met Val Phe Phe Leu Ile 350 355 360 Asn ProThr Lys Thr Phe Tyr Tyr Lys Ser Arg Phe Trp Leu Leu 365 370 375 Lys LeuLeu Phe Arg Val Phe Thr Ala Pro Phe His Lys Val Gly 380 385 390 Phe AlaAsp Phe Trp Leu Ala Asp Gln Leu Asn Ser Leu Ser Val 395 400 405 Ile LeuMet Asp Leu Glu Tyr Met Ile Cys Phe Tyr Ser Leu Glu 410 415 420 Leu LysTrp Asp Glu Ser Lys Gly Leu Leu Pro Asn Asn Ser Glu 425 430 435 Glu SerGly Ile Cys His Lys Tyr Thr Tyr Gly Val Arg Ala Ile 440 445 450 Val GlnCys Ile Pro Ala Trp Leu Arg Phe Ile Gln Cys Leu Arg 455 460 465 Arg TyrArg Asp Thr Lys Arg Ala Phe Pro His Leu Val Asn Ala 470 475 480 Gly LysTyr Ser Thr Thr Phe Phe Met Val Ala Phe Ala Ala Leu 485 490 495 Tyr SerThr His Lys Glu Arg Gly His Ser Asp Thr Met Val Phe 500 505 510 Phe TyrLeu Trp Ile Val Phe Tyr Ile Ile Ser Ser Cys Tyr Thr 515 520 525 Leu IleTrp Asp Leu Lys Met Asp Trp Gly Leu Phe Asp Lys Asn 530 535 540 Ala GlyGlu Asn Thr Phe Leu Arg Glu Glu Ile Val Tyr Pro Gln 545 550 555 Lys AlaTyr Tyr Tyr Cys Ala Ile Ile Glu Asp Val Ile Leu Arg 560 565 570 Phe AlaTrp Thr Ile Gln Ile Ser Ile Thr Ser Thr Thr Leu Leu 575 580 585 Pro HisSer Gly Asp Ile Ile Ala Thr Val Phe Ala Pro Leu Glu 590 595 600 Val PheArg Arg Phe Val Trp Asn Phe Phe Arg Leu Glu Asn Glu 605 610 615 His LeuAsn Asn Cys Gly Glu Phe Arg Ala Val Arg Asp Ile Ser 620 625 630 Val AlaPro Leu Asn Ala Asp Asp Gln Thr Leu Leu Glu Gln Met 635 640 645 Met AspGln Asp Asp Gly Val Arg Asn Arg Gln Lys Asn Arg Ser 650 655 660 Trp LysTyr Asn Gln Ser Ile Ser Leu Arg Arg Pro Arg Leu Ala 665 670 675 Ser GlnSer Lys Ala Arg Asp Thr Lys Val Leu Ile Glu Asp Thr 680 685 690 Asp AspGlu Ala Asn Thr 695 84 696 PRT Homo Sapien 84 Met Lys Phe Ala Glu HisLeu Ser Ala His Ile Thr Pro Glu Trp 1 5 10 15 Arg Lys Gln Tyr Ile GlnTyr Glu Ala Phe Lys Asp Met Leu Tyr 20 25 30 Ser Ala Gln Asp Gln Ala ProSer Val Glu Val Thr Asp Glu Asp 35 40 45 Thr Val Lys Arg Tyr Phe Ala LysPhe Glu Glu Lys Phe Phe Gln 50 55 60 Thr Cys Glu Lys Glu Leu Ala Lys IleAsn Thr Phe Tyr Ser Glu 65 70 75 Lys Leu Ala Glu Ala Gln Arg Arg Phe AlaThr Leu Gln Asn Glu 80 85 90 Leu Gln Ser Ser Leu Asp Ala Gln Lys Glu SerThr Gly Val Thr 95 100 105 Thr Leu Arg Gln Arg Arg Lys Pro Val Phe HisLeu Ser His Glu 110 115 120 Glu Arg Val Gln His Arg Asn Ile Lys Asp LeuLys Leu Ala Phe 125 130 135 Ser Glu Phe Tyr Leu Ser Leu Ile Leu Leu GlnAsn Tyr Gln Asn 140 145 150 Leu Asn Phe Thr Gly Phe Arg Lys Ile Leu LysLys His Asp Lys 155 160 165 Ile Leu Glu Thr Ser Arg Gly Ala Asp Trp ArgVal Ala His Val 170 175 180 Glu Val Ala Pro Phe Tyr Thr Cys Lys Lys IleAsn Gln Leu Ile 185 190 195 Ser Glu Thr Glu Ala Val Val Thr Asn Glu LeuGlu Asp Gly Asp 200 205 210 Arg Gln Lys Ala Met Lys Arg Leu Arg Val ProPro Leu Gly Ala 215 220 225 Ala Gln Pro Ala Pro Ala Trp Thr Thr Phe ArgVal Gly Leu Phe 230 235 240 Cys Gly Ile Phe Ile Val Leu Asn Ile Thr LeuVal Leu Ala Ala 245 250 255 Val Phe Lys Leu Glu Thr Asp Arg Ser Ile TrpPro Leu Ile Arg 260 265 270 Ile Tyr Arg Gly Gly Phe Leu Leu Ile Glu PheLeu Phe Leu Leu 275 280 285 Gly Ile Asn Thr Tyr Gly Trp Arg Gln Ala GlyVal Asn His Val 290 295 300 Leu Ile Phe Glu Leu Asn Pro Arg Ser Asn LeuSer His Gln His 305 310 315 Leu Phe Glu Ile Ala Gly Phe Leu Gly Ile LeuTrp Cys Leu Ser 320 325 330 Leu Leu Ala Cys Phe Phe Ala Pro Ile Ser ValIle Pro Thr Tyr 335 340 345 Val Tyr Pro Leu Ala Leu Tyr Gly Phe Met ValPhe Phe Leu Ile 350 355 360 Asn Pro Thr Lys Thr Phe Tyr Tyr Lys Ser ArgPhe Trp Leu Leu 365 370 375 Lys Leu Leu Phe Arg Val Phe Thr Ala Pro PheHis Lys Val Gly 380 385 390 Phe Ala Asp Phe Trp Leu Ala Asp Gln Leu AsnSer Leu Ser Val 395 400 405 Ile Leu Met Asp Leu Glu Tyr Met Ile Cys PheTyr Ser Leu Glu 410 415 420 Leu Lys Trp Asp Glu Ser Lys Gly Leu Leu ProAsn Asn Ser Glu 425 430 435 Glu Ser Gly Ile Cys His Lys Tyr Thr Tyr GlyVal Arg Ala Ile 440 445 450 Val Gln Cys Ile Pro Ala Trp Leu Arg Phe IleGln Cys Leu Arg 455 460 465 Arg Tyr Arg Asp Thr Lys Arg Ala Phe Pro HisLeu Val Asn Ala 470 475 480 Gly Lys Tyr Ser Thr Thr Phe Phe Met Val ThrPhe Ala Ala Leu 485 490 495 Tyr Ser Thr His Lys Glu Arg Gly His Ser AspThr Met Val Phe 500 505 510 Phe Tyr Leu Trp Ile Val Phe Tyr Ile Ile SerSer Cys Tyr Thr 515 520 525 Leu Ile Trp Asp Leu Lys Met Asp Trp Gly LeuPhe Asp Lys Asn 530 535 540 Ala Gly Glu Asn Thr Phe Leu Arg Glu Glu IleVal Tyr Pro Gln 545 550 555 Lys Ala Tyr Tyr Tyr Cys Ala Ile Ile Glu AspVal Ile Leu Arg 560 565 570 Phe Ala Trp Thr Ile Gln Ile Ser Ile Thr SerThr Thr Leu Leu 575 580 585 Pro His Ser Gly Asp Ile Ile Ala Thr Val PheAla Pro Leu Glu 590 595 600 Val Phe Arg Arg Phe Val Trp Asn Phe Phe ArgLeu Glu Asn Glu 605 610 615 His Leu Asn Asn Cys Gly Glu Phe Arg Ala ValArg Asp Ile Ser 620 625 630 Val Ala Pro Leu Asn Ala Asp Asp Gln Thr LeuLeu Glu Gln Met 635 640 645 Met Asp Gln Asp Asp Gly Val Arg Asn Arg GlnLys Asn Arg Ser 650 655 660 Trp Lys Tyr Asn Gln Ser Ile Ser Leu Arg ArgPro Arg Leu Ala 665 670 675 Ser Gln Ser Lys Ala Arg Asp Thr Lys Val LeuIle Glu Asp Thr 680 685 690 Asp Asp Glu Ala Asn Thr 695 85 635 PRT HomoSapien 85 Met Ser Val Gly Val Ser Thr Ser Ala Pro Leu Ser Pro Thr Ser 15 10 15 Gly Thr Ser Val Gly Met Ser Thr Phe Ser Ile Met Asp Tyr Val 2025 30 Val Phe Val Leu Leu Leu Val Leu Ser Leu Ala Ile Gly Leu Tyr 35 4045 His Ala Cys Arg Gly Trp Gly Arg His Thr Val Gly Glu Leu Leu 50 55 60Met Ala Asp Arg Lys Met Gly Cys Leu Pro Val Ala Leu Ser Leu 65 70 75 LeuAla Thr Phe Gln Ser Ala Val Ala Ile Leu Gly Val Pro Ser 80 85 90 Glu IleTyr Arg Phe Gly Thr Gln Tyr Trp Phe Leu Gly Cys Cys 95 100 105 Tyr PheLeu Gly Leu Leu Ile Pro Ala His Ile Phe Ile Pro Val 110 115 120 Phe TyrArg Leu His Leu Thr Ser Ala Tyr Glu Tyr Leu Glu Leu 125 130 135 Arg PheAsn Lys Thr Val Arg Val Cys Gly Thr Val Thr Phe Ile 140 145 150 Phe GlnMet Val Ile Tyr Met Gly Val Val Leu Tyr Ala Pro Ser 155 160 165 Leu AlaLeu Asn Ala Val Thr Gly Phe Asp Leu Trp Leu Ser Val 170 175 180 Leu AlaLeu Gly Ile Val Cys Thr Val Tyr Thr Ala Leu Gly Gly 185 190 195 Leu LysAla Val Ile Trp Thr Asp Val Phe Gln Thr Leu Val Met 200 205 210 Phe LeuGly Gln Leu Ala Val Ile Ile Val Gly Ser Ala Lys Val 215 220 225 Gly GlyLeu Gly Arg Val Trp Ala Val Ala Ser Gln His Gly Arg 230 235 240 Ile SerGly Phe Glu Leu Asp Pro Asp Pro Phe Val Arg His Thr 245 250 255 Phe TrpThr Leu Ala Phe Gly Gly Val Phe Met Met Leu Ser Leu 260 265 270 Tyr GlyVal Asn Gln Ala Gln Val Gln Arg Tyr Leu Ser Ser Arg 275 280 285 Thr GluLys Ala Ala Val Leu Ser Cys Tyr Ala Val Phe Pro Phe 290 295 300 Gln GlnVal Ser Leu Cys Val Gly Cys Leu Ile Gly Leu Val Met 305 310 315 Phe AlaTyr Tyr Gln Glu Tyr Pro Met Ser Ile Gln Gln Ala Gln 320 325 330 Ala AlaPro Asp Gln Phe Val Leu Tyr Phe Val Met Asp Leu Leu 335 340 345 Lys GlyLeu Pro Gly Leu Pro Gly Leu Phe Ile Ala Cys Leu Phe 350 355 360 Ser GlySer Leu Ser Thr Ile Ser Ser Ala Phe Asn Ser Leu Ala 365 370 375 Thr ValThr Met Glu Asp Leu Ile Arg Pro Trp Phe Pro Glu Phe 380 385 390 Ser GluAla Arg Ala Ile Met Leu Ser Arg Gly Leu Ala Phe Gly 395 400 405 Tyr GlyLeu Leu Cys Leu Gly Met Ala Tyr Ile Ser Ser Gln Met 410 415 420 Gly ProVal Leu Gln Ala Ala Ile Ser Ile Phe Gly Met Val Gly 425 430 435 Gly ProLeu Leu Gly Leu Phe Cys Leu Gly Met Phe Phe Pro Cys 440 445 450 Ala AsnPro Pro Gly Ala Val Val Gly Leu Leu Ala Gly Leu Val 455 460 465 Met AlaPhe Trp Ile Gly Ile Gly Ser Ile Val Thr Ser Met Gly 470 475 480 Phe SerMet Pro Pro Ser Pro Ser Asn Gly Ser Ser Phe Ser Leu 485 490 495 Pro ThrAsn Leu Thr Val Ala Thr Val Thr Thr Leu Met Pro Leu 500 505 510 Thr ThrPhe Ser Lys Pro Thr Gly Leu Gln Arg Phe Tyr Ser Leu 515 520 525 Ser TyrLeu Trp Tyr Ser Ala His Asn Ser Thr Thr Val Ile Val 530 535 540 Val GlyLeu Ile Val Ser Leu Leu Thr Gly Arg Met Arg Gly Arg 545 550 555 Ser LeuAsn Pro Ala Thr Ile Tyr Pro Val Leu Pro Lys Leu Leu 560 565 570 Ser LeuLeu Pro Leu Ser Cys Gln Lys Arg Leu His Cys Arg Ser 575 580 585 Tyr GlyGln Asp His Leu Asp Thr Gly Leu Phe Pro Glu Lys Pro 590 595 600 Arg AsnGly Val Leu Gly Asp Ser Arg Asp Lys Glu Ala Met Ala 605 610 615 Leu AspGly Thr Ala Tyr Gln Gly Ser Ser Ser Thr Cys Ile Leu 620 625 630 Gln GluThr Ser Leu 635 86 351 PRT Homo Sapien 86 Met Ala Leu Thr Gly Ala SerAsp Pro Ser Ala Glu Ala Glu Ala 1 5 10 15 Asn Gly Glu Lys Pro Phe LeuLeu Arg Ala Leu Gln Ile Ala Leu 20 25 30 Val Val Ser Leu Tyr Trp Val ThrSer Ile Ser Met Val Phe Leu 35 40 45 Asn Lys Tyr Leu Leu Asp Ser Pro SerLeu Arg Leu Asp Thr Pro 50 55 60 Ile Phe Val Thr Phe Tyr Gln Cys Leu ValThr Thr Leu Leu Cys 65 70 75 Lys Gly Leu Ser Ala Leu Ala Ala Cys Cys ProGly Ala Val Asp 80 85 90 Phe Pro Ser Leu Arg Leu Asp Leu Arg Val Ala ArgSer Val Leu 95 100 105 Pro Leu Ser Val Val Phe Ile Gly Met Ile Thr PheAsn Asn Leu 110 115 120 Cys Leu Lys Tyr Val Gly Val Ala Phe Tyr Asn ValGly Arg Ser 125 130 135 Leu Thr Thr Val Phe Asn Val Leu Leu Ser Tyr LeuLeu Leu Lys 140 145 150 Gln Thr Thr Ser Phe Tyr Ala Leu Leu Thr Cys GlyIle Ile Ile 155 160 165 Gly Gly Phe Trp Leu Gly Val Asp Gln Glu Gly AlaGlu Gly Thr 170 175 180 Leu Ser Trp Leu Gly Thr Val Phe Gly Val Leu AlaSer Leu Cys 185 190 195 Val Ser Leu Asn Ala Ile Tyr Thr Thr Lys Val LeuPro Ala Val 200 205 210 Asp Gly Ser Ile Trp Arg Leu Thr Phe Tyr Asn AsnVal Asn Ala 215 220 225 Cys Ile Leu Phe Leu Pro Leu Leu Leu Leu Leu GlyGlu Leu Gln 230 235 240 Ala Leu Arg Asp Leu Ala Gln Leu Gly Ser Ala HisPhe Trp Gly 245 250 255 Met Met Thr Leu Gly Gly Leu Phe Gly Phe Ala IleGly Tyr Val 260 265 270 Thr Gly Leu Gln Ile Lys Phe Thr Ser Pro Leu ThrHis Asn Val 275 280 285 Ser Gly Thr Ala Lys Ala Cys Ala Gln Thr Val LeuAla Val Leu 290 295 300 Tyr Tyr Glu Glu Thr Lys Ser Phe Leu Trp Trp ThrSer Asn Met 305 310 315 Met Val Leu Gly Gly Ser Ser Ala Tyr Thr Trp ValArg Gly Trp 320 325 330 Glu Met Lys Lys Thr Pro Glu Glu Pro Ser Pro LysAsp Ser Glu 335 340 345 Lys Ser Ala Met Gly Val 350 87 351 PRT HomoSapien 87 Met Ala Leu Thr Gly Ala Ser Asp Pro Ser Ala Glu Ala Glu Ala 15 10 15 Asn Gly Glu Lys Pro Phe Leu Leu Arg Ala Leu Gln Ile Ala Leu 2025 30 Val Val Ser Leu Tyr Trp Val Thr Ser Ile Ser Met Val Phe Leu 35 4045 Asn Lys Tyr Leu Leu Asp Ser Pro Ser Leu Arg Leu Asp Thr Pro 50 55 60Ile Phe Val Thr Phe Tyr Gln Cys Leu Val Thr Thr Leu Leu Cys 65 70 75 LysGly Leu Ser Ala Leu Ala Ala Cys Cys Pro Gly Ala Val Asp 80 85 90 Phe ProSer Leu Arg Leu Asp Leu Arg Val Ala Arg Ser Val Leu 95 100 105 Pro LeuSer Val Val Phe Ile Gly Met Ile Thr Phe Asn Asn Leu 110 115 120 Cys LeuLys Tyr Val Gly Val Ala Phe Tyr Asn Val Gly Arg Ser 125 130 135 Leu ThrThr Val Phe Asn Val Leu Leu Ser Tyr Leu Leu Leu Lys 140 145 150 Gln ThrThr Ser Phe Tyr Ala Leu Leu Thr Cys Gly Ile Ile Ile 155 160 165 Gly GlyPhe Trp Leu Gly Val Asp Gln Glu Gly Ala Glu Gly Thr 170 175 180 Leu SerTrp Leu Gly Thr Val Phe Gly Val Leu Ala Ser Leu Cys 185 190 195 Val SerLeu Asn Ala Ile Tyr Thr Thr Lys Val Leu Pro Ala Val 200 205 210 Asp GlySer Ile Trp Arg Leu Thr Phe Tyr Asn Asn Val Asn Ala 215 220 225 Cys IleLeu Phe Leu Pro Leu Leu Leu Leu Leu Gly Glu Leu Gln 230 235 240 Ala LeuArg Asp Phe Ala Gln Leu Gly Ser Ala His Phe Trp Gly 245 250 255 Met MetThr Leu Gly Gly Leu Phe Gly Phe Ala Ile Gly Tyr Val 260 265 270 Thr GlyLeu Gln Ile Lys Phe Thr Ser Pro Leu Thr His Asn Val 275 280 285 Ser GlyThr Ala Lys Ala Cys Ala Gln Thr Val Leu Ala Val Leu 290 295 300 Tyr TyrGlu Glu Thr Lys Ser Phe Leu Trp Trp Thr Ser Asn Met 305 310 315 Met ValLeu Gly Gly Ser Ser Ala Tyr Thr Trp Val Arg Gly Trp 320 325 330 Glu MetLys Lys Thr Pro Glu Glu Pro Ser Pro Lys Asp Ser Glu 335 340 345 Lys SerAla Met Gly Val 350 88 208 PRT Homo Sapien 88 Met Gly Ser Cys Ser GlyArg Cys Ala Leu Val Val Leu Cys Ala 1 5 10 15 Phe Gln Leu Val Ala AlaLeu Glu Arg Gln Val Phe Asp Phe Leu 20 25 30 Gly Tyr Gln Trp Ala Pro IleLeu Ala Asn Phe Val His Ile Ile 35 40 45 Ile Val Ile Leu Gly Leu Phe GlyThr Ile Gln Tyr Arg Leu Arg 50 55 60 Tyr Val Met Val Tyr Thr Leu Trp AlaAla Val Trp Val Thr Trp 65 70 75 Asn Val Phe Ile Ile Cys Phe Tyr Leu GluVal Gly Gly Leu Leu 80 85 90 Gln Asp Ser Glu Leu Leu Thr Phe Ser Leu SerArg His Arg Ser 95 100 105 Trp Trp Arg Glu Arg Trp Pro Gly Cys Leu HisGlu Glu Val Pro 110 115 120 Ala Val Gly Leu Gly Ala Pro His Gly Gln AlaLeu Val Ser Gly 125 130 135 Ala Gly Cys Ala Leu Glu Pro Ser Tyr Val GluAla Leu His Ser 140 145 150 Gly Leu Gln Ile Leu Ile Ala Leu Leu Gly PheVal Cys Gly Cys 155 160 165 Gln Val Val Ser Val Phe Thr Glu Glu Glu AspSer Phe Asp Phe 170 175 180 Ile Gly Gly Phe Asp Pro Phe Pro Leu Tyr HisVal Asn Glu Lys 185 190 195 Pro Ser Ser Leu Leu Ser Lys Gln Val Tyr LeuPro Ala 200 205 89 208 PRT Homo Sapien 89 Met Gly Ser Cys Ser Gly ArgCys Ala Leu Val Val Leu Cys Ala 1 5 10 15 Phe Gln Leu Val Ala Ala LeuGlu Arg Gln Val Phe Asp Phe Leu 20 25 30 Gly Tyr Gln Trp Ala Pro Ile LeuAla Asn Phe Val His Ile Ile 35 40 45 Ile Val Ile Leu Gly Leu Phe Gly ThrIle Gln Tyr Arg Leu Arg 50 55 60 Tyr Val Met Val Tyr Thr Leu Trp Ala AlaVal Trp Val Thr Trp 65 70 75 Asn Val Phe Ile Ile Cys Phe Tyr Leu Glu ValGly Gly Leu Leu 80 85 90 Lys Asp Ser Glu Leu Leu Thr Phe Ser Leu Ser ArgHis Arg Ser 95 100 105 Trp Trp Arg Glu Arg Trp Pro Gly Cys Leu His GluGlu Val Pro 110 115 120 Ala Val Gly Leu Gly Ala Pro His Gly Gln Ala LeuVal Ser Gly 125 130 135 Ala Gly Cys Ala Leu Glu Pro Ser Tyr Val Glu AlaLeu His Ser 140 145 150 Cys Leu Gln Ile Leu Ile Ala Leu Leu Gly Phe ValCys Gly Cys 155 160 165 Gln Val Val Ser Val Phe Thr Glu Glu Glu Asp SerPhe Asp Phe 170 175 180 Ile Gly Gly Phe Asp Pro Phe Pro Leu Tyr His ValAsn Glu Lys 185 190 195 Pro Ser Ser Leu Leu Ser Lys Gln Val Tyr Leu ProAla 200 205 90 181 PRT Homo Sapien 90 Met Gly Ser Cys Ser Gly Arg CysAla Leu Val Val Leu Cys Ala 1 5 10 15 Phe Gln Leu Val Ala Ala Leu GluArg Gln Val Phe Asp Phe Leu 20 25 30 Gly Tyr Gln Trp Ala Pro Ile Leu AlaAsn Phe Val His Ile Ile 35 40 45 Ile Val Ile Leu Gly Leu Phe Gly Thr IleGln Tyr Arg Leu Arg 50 55 60 Tyr Val Met Val Tyr Thr Leu Trp Ala Ala ValTrp Val Thr Trp 65 70 75 Asn Val Phe Ile Ile Cys Phe Tyr Leu Glu Val GlyGly Leu Leu 80 85 90 Lys Asp Ser Glu Leu Leu Thr Phe Ser Leu Ser Arg HisArg Ser 95 100 105 Trp Trp Arg Glu Arg Trp Pro Gly Cys Leu His Glu GluVal Pro 110 115 120 Ala Val Gly Leu Gly Ala Pro His Gly Gln Ala Leu ValSer Gly 125 130 135 Ala Gly Cys Ala Leu Glu Pro Ser Tyr Val Glu Ala LeuHis Ser 140 145 150 Cys Leu Gln Ile Leu Ile Ala Leu Leu Gly Phe Val CysGly Cys 155 160 165 Gln Val Val Ser Val Phe Thr Glu Glu Glu Asp Ser CysLeu Arg 170 175 180 Lys 91 181 PRT Homo Sapien 91 Met Gly Ser Cys SerGly Arg Cys Ala Leu Val Val Leu Cys Ala 1 5 10 15 Phe Gln Leu Val AlaAla Leu Glu Arg Gln Val Phe Asp Phe Leu 20 25 30 Gly Tyr Gln Trp Ala ProIle Leu Ala Asn Phe Val His Ile Ile 35 40 45 Ile Val Ile Leu Gly Leu PheGly Thr Ile Gln Tyr Arg Leu Arg 50 55 60 Tyr Val Met Val Tyr Thr Leu TrpAla Ala Val Trp Val Thr Trp 65 70 75 Asn Val Phe Ile Ile Cys Phe Tyr LeuGlu Val Gly Gly Leu Leu 80 85 90 Gln Asp Ser Glu Leu Leu Thr Phe Ser LeuSer Arg His Arg Ser 95 100 105 Trp Trp Arg Glu Arg Trp Pro Gly Cys LeuHis Glu Glu Val Pro 110 115 120 Ala Val Gly Leu Gly Ala Pro His Gly GlnAla Leu Val Ser Gly 125 130 135 Ala Gly Cys Ala Leu Glu Pro Ser Tyr ValGlu Ala Leu His Ser 140 145 150 Gly Leu Gln Ile Leu Ile Ala Leu Leu GlyPhe Val Cys Gly Cys 155 160 165 Gln Val Val Ser Val Phe Thr Glu Glu GluAsp Ser Cys Leu Arg 170 175 180 Lys 92 382 PRT Homo Sapien 92 Met AlaVal Leu Phe Leu Leu Leu Phe Leu Cys Gly Thr Pro Gln 1 5 10 15 Ala AlaAsp Asn Met Gln Ala Ile Tyr Val Ala Leu Gly Glu Ala 20 25 30 Val Glu LeuPro Cys Pro Ser Pro Pro Thr Leu His Gly Asp Glu 35 40 45 His Leu Ser TrpPhe Cys Ser Pro Ala Ala Gly Ser Phe Thr Thr 50 55 60 Leu Val Ala Gln ValGln Val Gly Arg Pro Ala Pro Asp Pro Gly 65 70 75 Lys Pro Gly Arg Glu SerArg Leu Arg Leu Leu Gly Asn Tyr Ser 80 85 90 Leu Trp Leu Glu Gly Ser LysGlu Glu Asp Ala Gly Arg Tyr Trp 95 100 105 Cys Ala Val Leu Gly Gln HisHis Asn Tyr Gln Asn Trp Arg Val 110 115 120 Tyr Asp Val Leu Val Leu LysGly Ser Gln Leu Ser Ala Arg Ala 125 130 135 Ala Asp Gly Ser Pro Cys AsnVal Leu Leu Cys Ser Val Val Pro 140 145 150 Ser Arg Arg Met Asp Ser ValThr Trp Gln Glu Gly Lys Gly Pro 155 160 165 Val Arg Gly Arg Val Gln SerPhe Trp Gly Ser Glu Ala Ala Leu 170 175 180 Leu Leu Val Cys Pro Gly GluGly Leu Ser Glu Pro Arg Ser Arg 185 190 195 Arg Pro Arg Ile Ile Arg CysLeu Met Thr His Asn Lys Gly Val 200 205 210 Ser Phe Ser Leu Ala Ala SerIle Asp Ala Ser Pro Ala Leu Cys 215 220 225 Ala Pro Ser Thr Gly Trp AspMet Pro Trp Ile Leu Met Leu Leu 230 235 240 Leu Thr Met Gly Gln Gly ValVal Ile Leu Ala Leu Ser Ile Val 245 250 255 Leu Trp Arg Gln Arg Val ArgGly Ala Pro Gly Arg Gly Asn Arg 260 265 270 Met Arg Cys Tyr Asn Cys GlyGly Ser Pro Ser Ser Ser Cys Lys 275 280 285 Glu Ala Val Thr Thr Cys GlyGlu Gly Arg Pro Gln Pro Gly Leu 290 295 300 Glu Gln Ile Lys Leu Pro GlyAsn Pro Pro Val Thr Leu Ile His 305 310 315 Gln His Pro Ala Cys Val AlaAla His His Cys Asn Gln Val Glu 320 325 330 Thr Glu Ser Val Gly Asp ValThr Tyr Pro Ala His Arg Asp Cys 335 340 345 Tyr Leu Gly Asp Leu Cys AsnSer Ala Val Ala Ser His Val Ala 350 355 360 Pro Ala Gly Ile Leu Ala AlaAla Ala Thr Ala Leu Thr Cys Leu 365 370 375 Leu Pro Gly Leu Trp Ser Gly380 93 783 PRT Homo Sapien 93 Met Ser Gly Gly His Gln Leu Gln Leu AlaAla Leu Trp Pro Trp 1 5 10 15 Leu Leu Met Ala Thr Leu Gln Ala Gly PheGly Arg Thr Gly Leu 20 25 30 Val Leu Ala Ala Ala Val Glu Ser Glu Arg SerAla Glu Gln Lys 35 40 45 Ala Val Ile Arg Val Ile Pro Leu Lys Met Asp ProThr Gly Lys 50 55 60 Leu Asn Leu Thr Leu Glu Gly Val Phe Ala Gly Val AlaGlu Ile 65 70 75 Thr Pro Ala Glu Gly Lys Leu Met Gln Ser His Pro Leu TyrLeu 80 85 90 Cys Asn Ala Ser Asp Asp Asp Asn Leu Glu Pro Gly Phe Ile Ser95 100 105 Ile Val Lys Leu Glu Ser Pro Arg Arg Ala Pro Arg Pro Cys Leu110 115 120 Ser Leu Ala Ser Lys Ala Arg Met Ala Gly Glu Arg Gly Ala Ser125 130 135 Ala Val Leu Phe Asp Ile Thr Glu Asp Arg Ala Ala Ala Glu Gln140 145 150 Leu Gln Gln Pro Leu Gly Leu Thr Trp Pro Val Val Leu Ile Trp155 160 165 Gly Asn Asp Ala Glu Lys Leu Met Glu Phe Val Tyr Lys Asn Gln170 175 180 Lys Ala His Val Arg Ile Glu Leu Lys Glu Pro Pro Ala Trp Pro185 190 195 Asp Tyr Asp Val Trp Ile Leu Met Thr Val Val Gly Thr Ile Phe200 205 210 Val Ile Ile Leu Ala Ser Val Leu Arg Ile Arg Cys Arg Pro Arg215 220 225 His Ser Arg Pro Asp Pro Leu Gln Gln Arg Thr Ala Trp Ala Ile230 235 240 Ser Gln Leu Ala Thr Arg Arg Tyr Gln Ala Ser Cys Arg Gln Ala245 250 255 Arg Gly Glu Trp Pro Asp Ser Gly Ser Ser Cys Ser Ser Ala Pro260 265 270 Val Cys Ala Ile Cys Leu Glu Glu Phe Ser Glu Gly Gln Glu Leu275 280 285 Arg Val Ile Ser Cys Leu His Glu Phe His Arg Asn Cys Val Asp290 295 300 Pro Trp Leu His Gln His Arg Thr Cys Pro Leu Cys Val Phe Asn305 310 315 Ile Thr Glu Gly Asp Ser Phe Ser Gln Ser Leu Gly Pro Ser Arg320 325 330 Ser Tyr Gln Glu Pro Gly Arg Arg Leu His Leu Ile Arg Gln His335 340 345 Pro Gly His Ala His Tyr His Leu Pro Ala Ala Tyr Leu Leu Gly350 355 360 Pro Ser Arg Ser Ala Val Ala Arg Pro Pro Arg Pro Gly Pro Phe365 370 375 Leu Pro Ser Gln Glu Pro Gly Met Gly Pro Arg His His Arg Phe380 385 390 Pro Arg Ala Ala His Pro Arg Ala Pro Gly Glu Gln Gln Arg Leu395 400 405 Ala Gly Ala Gln His Pro Tyr Ala Gln Gly Trp Gly Met Ser His410 415 420 Leu Gln Ser Thr Ser Gln His Pro Ala Ala Cys Pro Val Pro Leu425 430 435 Arg Arg Ala Arg Pro Pro Asp Ser Ser Gly Ser Gly Glu Ser Tyr440 445 450 Cys Thr Glu Arg Ser Gly Tyr Leu Ala Asp Gly Pro Ala Ser Asp455 460 465 Ser Ser Ser Gly Pro Cys His Gly Ser Ser Ser Asp Ser Val Val470 475 480 Asn Cys Thr Asp Ile Ser Leu Gln Gly Val His Gly Ser Ser Ser485 490 495 Thr Phe Cys Ser Ser Leu Ser Ser Asp Phe Asp Pro Leu Val Tyr500 505 510 Cys Ser Pro Lys Gly Asp Pro Gln Arg Val Asp Met Gln Pro Ser515 520 525 Val Thr Ser Arg Pro Arg Ser Leu Asp Ser Val Val Pro Thr Gly530 535 540 Glu Thr Gln Val Ser Ser His Val His Tyr His Arg His Arg His545 550 555 His His Tyr Lys Lys Arg Phe Gln Trp His Gly Arg Lys Pro Gly560 565 570 Pro Glu Thr Gly Val Pro Gln Ser Arg Pro Pro Ile Pro Arg Thr575 580 585 Gln Pro Gln Pro Glu Pro Pro Ser Pro Asp Gln Gln Val Thr Gly590 595 600 Ser Asn Ser Ala Ala Pro Ser Gly Arg Leu Ser Asn Pro Gln Cys605 610 615 Pro Arg Ala Leu Pro Glu Pro Ala Pro Gly Pro Val Asp Ala Ser620 625 630 Ser Ile Cys Pro Ser Thr Ser Ser Leu Phe Asn Leu Gln Lys Ser635 640 645 Ser Leu Ser Ala Arg His Pro Gln Arg Lys Arg Arg Gly Gly Pro650 655 660 Ser Glu Pro Thr Pro Gly Ser Arg Pro Gln Asp Ala Thr Val His665 670 675 Pro Ala Cys Gln Ile Phe Pro His Tyr Thr Pro Ser Val Ala Tyr680 685 690 Pro Trp Ser Pro Glu Ala His Pro Leu Ile Cys Gly Pro Pro Gly695 700 705 Leu Asp Lys Arg Leu Leu Pro Glu Thr Pro Gly Pro Cys Tyr Ser710 715 720 Asn Ser Gln Pro Val Trp Leu Cys Leu Thr Pro Arg Gln Pro Leu725 730 735 Glu Pro His Pro Pro Gly Glu Gly Pro Ser Glu Trp Ser Ser Asp740 745 750 Thr Ala Glu Gly Arg Pro Cys Pro Tyr Pro His Cys Gln Val Leu755 760 765 Ser Ala Gln Pro Gly Ser Glu Glu Glu Leu Glu Glu Leu Cys Glu770 775 780 Gln Ala Val 94 510 PRT Homo Sapien 94 Met Pro Leu Ser LeuGly Ala Glu Met Trp Gly Pro Glu Ala Trp 1 5 10 15 Leu Leu Leu Leu LeuLeu Leu Ala Ser Phe Thr Gly Arg Cys Pro 20 25 30 Ala Gly Glu Leu Glu ThrSer Asp Val Val Thr Val Val Leu Gly 35 40 45 Gln Asp Ala Lys Leu Pro CysPhe Tyr Arg Gly Asp Ser Gly Glu 50 55 60 Gln Val Gly Gln Val Ala Trp AlaArg Val Asp Ala Gly Glu Gly 65 70 75 Ala Gln Glu Leu Ala Leu Leu His SerLys Tyr Gly Leu His Val 80 85 90 Ser Pro Ala Tyr Glu Gly Arg Val Glu GlnPro Pro Pro Pro Arg 95 100 105 Asn Pro Leu Asp Gly Ser Val Leu Leu ArgAsn Ala Val Gln Ala 110 115 120 Asp Glu Gly Glu Tyr Glu Cys Arg Val SerThr Phe Pro Ala Gly 125 130 135 Ser Phe Gln Ala Arg Leu Arg Leu Arg ValLeu Val Pro Pro Leu 140 145 150 Pro Ser Leu Asn Pro Gly Pro Ala Leu GluGlu Gly Gln Gly Leu 155 160 165 Thr Leu Ala Ala Ser Cys Thr Ala Glu GlySer Pro Ala Pro Ser 170 175 180 Val Thr Trp Asp Thr Glu Val Lys Gly ThrThr Ser Ser Arg Ser 185 190 195 Phe Lys His Ser Arg Ser Ala Ala Val ThrSer Glu Phe His Leu 200 205 210 Val Pro Ser Arg Ser Met Asn Gly Gln ProLeu Thr Cys Val Val 215 220 225 Ser His Pro Gly Leu Leu Gln Asp Gln ArgIle Thr His Ile Leu 230 235 240 His Val Ser Phe Leu Ala Glu Ala Ser ValArg Gly Leu Glu Asp 245 250 255 Gln Asn Leu Trp His Ile Gly Arg Glu GlyAla Met Leu Lys Cys 260 265 270 Leu Ser Glu Gly Gln Pro Pro Pro Ser TyrAsn Trp Thr Arg Leu 275 280 285 Asp Gly Pro Leu Pro Ser Gly Val Arg ValAsp Gly Asp Thr Leu 290 295 300 Gly Phe Pro Pro Leu Thr Thr Glu His SerGly Ile Tyr Val Cys 305 310 315 His Val Ser Asn Glu Phe Ser Ser Arg AspSer Gln Val Thr Val 320 325 330 Asp Val Leu Asp Pro Gln Glu Asp Ser GlyLys Gln Val Asp Leu 335 340 345 Val Ser Ala Ser Val Val Val Val Gly ValIle Ala Ala Leu Leu 350 355 360 Phe Cys Leu Leu Val Val Val Val Val LeuMet Ser Arg Tyr His 365 370 375 Arg Arg Lys Ala Gln Gln Met Thr Gln LysTyr Glu Glu Glu Leu 380 385 390 Thr Leu Thr Arg Glu Asn Ser Ile Arg ArgLeu His Ser His His 395 400 405 Thr Asp Pro Arg Ser Gln Pro Glu Glu SerVal Gly Leu Arg Ala 410 415 420 Glu Gly His Pro Asp Ser Leu Lys Asp AsnSer Ser Cys Ser Val 425 430 435 Met Ser Glu Glu Pro Glu Gly Arg Ser TyrSer Thr Leu Thr Thr 440 445 450 Val Arg Glu Ile Glu Thr Gln Thr Glu LeuLeu Ser Pro Gly Ser 455 460 465 Gly Arg Ala Glu Glu Glu Glu Asp Gln AspGlu Gly Ile Lys Gln 470 475 480 Ala Met Asn His Phe Val Gln Glu Asn GlyThr Leu Arg Ala Lys 485 490 495 Pro Thr Gly Asn Gly Ile Tyr Ile Asn GlyArg Gly His Leu Val 500 505 510 95 523 PRT Homo Sapien 95 Met Thr GlnAsn Lys Leu Lys Leu Cys Ser Lys Ala Asn Val Tyr 1 5 10 15 Thr Glu ValPro Asp Gly Gly Trp Gly Trp Ala Val Ala Val Ser 20 25 30 Phe Phe Phe ValGlu Val Phe Thr Tyr Gly Ile Ile Lys Thr Phe 35 40 45 Gly Val Phe Phe AsnAsp Leu Met Asp Ser Phe Asn Glu Ser Asn 50 55 60 Ser Arg Ile Ser Trp IleIle Ser Ile Cys Val Phe Val Leu Thr 65 70 75 Phe Ser Ala Pro Leu Ala ThrVal Leu Ser Asn Arg Phe Gly His 80 85 90 Arg Leu Val Val Met Leu Gly GlyLeu Leu Val Ser Thr Gly Met 95 100 105 Val Ala Ala Ser Phe Ser Gln GluVal Ser His Met Tyr Val Ala 110 115 120 Ile Gly Ile Ile Ser Gly Leu GlyTyr Cys Phe Ser Phe Leu Pro 125 130 135 Thr Val Thr Ile Leu Ser Gln TyrPhe Gly Lys Arg Arg Ser Ile 140 145 150 Val Thr Ala Val Ala Ser Thr GlyGlu Cys Phe Ala Val Phe Ala 155 160 165 Phe Ala Pro Ala Ile Met Ala LeuLys Glu Arg Ile Gly Trp Arg 170 175 180 Tyr Ser Leu Leu Phe Val Gly LeuLeu Gln Leu Asn Ile Val Ile 185 190 195 Phe Gly Ala Leu Leu Arg Pro IleIle Ile Arg Gly Pro Ala Ser 200 205 210 Pro Lys Ile Val Ile Gln Glu AsnArg Lys Glu Ala Gln Tyr Met 215 220 225 Leu Glu Asn Glu Lys Thr Arg ThrSer Ile Asp Ser Ile Asp Ser 230 235 240 Gly Val Glu Leu Thr Thr Ser ProLys Asn Val Pro Thr His Thr 245 250 255 Asn Leu Glu Leu Glu Pro Lys AlaAsp Met Gln Gln Val Leu Val 260 265 270 Lys Thr Ser Pro Arg Pro Ser GluLys Lys Ala Pro Leu Leu Asp 275 280 285 Phe Ser Ile Leu Lys Glu Lys SerPhe Ile Cys Tyr Ala Leu Phe 290 295 300 Gly Leu Phe Ala Thr Leu Gly PhePhe Ala Pro Ser Leu Tyr Ile 305 310 315 Ile Pro Leu Gly Ile Ser Leu GlyIle Asp Gln Asp Arg Ala Ala 320 325 330 Phe Leu Leu Ser Thr Met Ala IleAla Glu Val Phe Gly Arg Ile 335 340 345 Gly Ala Gly Phe Val Leu Asn ArgGlu Pro Ile Arg Lys Ile Tyr 350 355 360 Ile Glu Leu Ile Cys Val Ile LeuLeu Thr Val Ser Leu Phe Ala 365 370 375 Phe Thr Phe Ala Thr Glu Phe TrpGly Leu Met Ser Cys Ser Ile 380 385 390 Phe Phe Gly Phe Met Val Gly ThrIle Gly Gly Leu Thr Phe His 395 400 405 Cys Leu Leu Lys Met Met Ser TrpAla Leu Gln Lys Met Ser Ser 410 415 420 Ala Ala Gly Val Tyr Ile Phe IleGln Ser Ile Ala Gly Leu Ala 425 430 435 Gly Pro Pro Leu Ala Gly Leu LeuVal Asp Gln Ser Lys Ile Tyr 440 445 450 Ser Arg Ala Phe Tyr Ser Cys AlaAla Gly Met Ala Leu Ala Ala 455 460 465 Val Cys Leu Ala Leu Val Arg ProCys Lys Met Gly Leu Cys Gln 470 475 480 Arg His His Ser Gly Glu Thr LysVal Val Ser His Arg Gly Lys 485 490 495 Thr Leu Gln Asp Ile Pro Glu AspPhe Leu Glu Met Asp Leu Ala 500 505 510 Lys Asn Glu His Arg Val His ValGln Met Glu Pro Val 515 520 96 124 PRT Homo Sapien 96 Met Leu Leu TrpVal Ile Leu Leu Val Leu Ala Pro Val Ser Gly 1 5 10 15 Gln Phe Ala ArgThr Pro Arg Pro Ile Ile Phe Leu Gln Pro Pro 20 25 30 Trp Thr Thr Val PheGln Gly Glu Arg Val Thr Leu Thr Cys Lys 35 40 45 Gly Phe Arg Phe Tyr SerPro Gln Lys Thr Lys Trp Tyr His Arg 50 55 60 Tyr Leu Gly Lys Glu Ile LeuArg Glu Thr Pro Asp Asn Ile Leu 65 70 75 Glu Val Gln Glu Ser Gly Glu TyrArg Cys Gln Ala Gln Gly Ser 80 85 90 Pro Leu Ser Ser Pro Val His Leu AspPhe Ser Ser Glu Met Gly 95 100 105 Phe Pro His Ala Ala Gln Ala Asn ValGlu Leu Leu Gly Ser Ser 110 115 120 Asp Leu Leu Thr 97 977 PRT HomoSapien 97 Met Leu Leu Trp Val Ile Leu Leu Val Leu Ala Pro Val Ser Gly 15 10 15 Gln Phe Ala Arg Thr Pro Arg Pro Ile Ile Phe Leu Gln Pro Pro 2025 30 Trp Thr Thr Val Phe Gln Gly Glu Arg Val Thr Leu Thr Cys Lys 35 4045 Gly Phe Arg Phe Tyr Ser Pro Gln Lys Thr Lys Trp Tyr His Arg 50 55 60Tyr Leu Gly Lys Glu Ile Leu Arg Glu Thr Pro Asp Asn Ile Leu 65 70 75 GluVal Gln Glu Ser Gly Glu Tyr Arg Cys Gln Ala Gln Gly Ser 80 85 90 Pro LeuSer Ser Pro Val His Leu Asp Phe Ser Ser Ala Ser Leu 95 100 105 Ile LeuGln Ala Pro Leu Ser Val Phe Glu Gly Asp Ser Val Val 110 115 120 Leu ArgCys Arg Ala Lys Ala Glu Val Thr Leu Asn Asn Thr Ile 125 130 135 Tyr LysAsn Asp Asn Val Leu Ala Phe Leu Asn Lys Arg Thr Asp 140 145 150 Phe HisIle Pro His Ala Cys Leu Lys Asp Asn Gly Ala Tyr Arg 155 160 165 Cys ThrGly Tyr Lys Glu Ser Cys Cys Pro Val Ser Ser Asn Thr 170 175 180 Val LysIle Gln Val Gln Glu Pro Phe Thr Arg Pro Val Leu Arg 185 190 195 Ala SerSer Phe Gln Pro Ile Ser Gly Asn Pro Val Thr Leu Thr 200 205 210 Cys GluThr Gln Leu Ser Leu Glu Arg Ser Asp Val Pro Leu Arg 215 220 225 Phe ArgPhe Phe Arg Asp Asp Gln Thr Leu Gly Leu Gly Trp Ser 230 235 240 Leu SerPro Asn Phe Gln Ile Thr Ala Met Trp Ser Lys Asp Ser 245 250 255 Gly PheTyr Trp Cys Lys Ala Ala Thr Met Pro His Ser Val Ile 260 265 270 Ser AspSer Pro Arg Ser Trp Ile Gln Val Gln Ile Pro Ala Ser 275 280 285 His ProVal Leu Thr Leu Ser Pro Glu Lys Ala Leu Asn Phe Glu 290 295 300 Gly ThrLys Val Thr Leu His Cys Glu Thr Gln Glu Asp Ser Leu 305 310 315 Arg ThrLeu Tyr Arg Phe Tyr His Glu Gly Val Pro Leu Arg His 320 325 330 Lys SerVal Arg Cys Glu Arg Gly Ala Ser Ile Ser Phe Ser Leu 335 340 345 Thr ThrGlu Asn Ser Gly Asn Tyr Tyr Cys Thr Ala Asp Asn Gly 350 355 360 Leu GlyAla Lys Pro Ser Lys Ala Val Ser Leu Ser Val Thr Val 365 370 375 Pro ValSer His Pro Val Leu Asn Leu Ser Ser Pro Glu Asp Leu 380 385 390 Ile PheGlu Gly Ala Lys Val Thr Leu His Cys Glu Ala Gln Arg 395 400 405 Gly SerLeu Pro Ile Leu Tyr Gln Phe His His Glu Asp Ala Ala 410 415 420 Leu GluArg Arg Ser Ala Asn Ser Ala Gly Gly Val Ala Ile Ser 425 430 435 Phe SerLeu Thr Ala Glu His Ser Gly Asn Tyr Tyr Cys Thr Ala 440 445 450 Asp AsnGly Phe Gly Pro Gln Arg Ser Lys Ala Val Ser Leu Ser 455 460 465 Ile ThrVal Pro Val Ser His Pro Val Leu Thr Leu Ser Ser Ala 470 475 480 Glu AlaLeu Thr Phe Glu Gly Ala Thr Val Thr Leu His Cys Glu 485 490 495 Val GlnArg Gly Ser Pro Gln Ile Leu Tyr Gln Phe Tyr His Glu 500 505 510 Asp MetPro Leu Trp Ser Ser Ser Thr Pro Ser Val Gly Arg Val 515 520 525 Ser PheSer Phe Ser Leu Thr Glu Gly His Ser Gly Asn Tyr Tyr 530 535 540 Cys ThrAla Asp Asn Gly Phe Gly Pro Gln Arg Ser Glu Val Val 545 550 555 Ser LeuPhe Val Thr Val Pro Val Ser Arg Pro Ile Leu Thr Leu 560 565 570 Arg ValPro Arg Ala Gln Ala Val Val Gly Asp Leu Leu Glu Leu 575 580 585 His CysGlu Ala Pro Arg Gly Ser Pro Pro Ile Leu Tyr Trp Phe 590 595 600 Tyr HisGlu Asp Val Thr Leu Gly Ser Ser Ser Ala Pro Ser Gly 605 610 615 Gly GluAla Ser Phe Asn Leu Ser Leu Thr Ala Glu His Ser Gly 620 625 630 Asn TyrSer Cys Glu Ala Asn Asn Gly Leu Val Ala Gln His Ser 635 640 645 Asp ThrIle Ser Leu Ser Val Ile Val Pro Val Ser Arg Pro Ile 650 655 660 Leu ThrPhe Arg Ala Pro Arg Ala Gln Ala Val Val Gly Asp Leu 665 670 675 Leu GluLeu His Cys Glu Ala Leu Arg Gly Ser Ser Pro Ile Leu 680 685 690 Tyr TrpPhe Tyr His Glu Asp Val Thr Leu Gly Lys Ile Ser Ala 695 700 705 Pro SerGly Gly Gly Ala Ser Phe Asn Leu Ser Leu Thr Thr Glu 710 715 720 His SerGly Ile Tyr Ser Cys Glu Ala Asp Asn Gly Pro Glu Ala 725 730 735 Gln ArgSer Glu Met Val Thr Leu Lys Val Ala Val Pro Val Ser 740 745 750 Arg ProVal Leu Thr Leu Arg Ala Pro Gly Thr His Ala Ala Val 755 760 765 Gly AspLeu Leu Glu Leu His Cys Glu Ala Leu Arg Gly Ser Pro 770 775 780 Leu IleLeu Tyr Arg Phe Phe His Glu Asp Val Thr Leu Gly Asn 785 790 795 Arg SerSer Pro Ser Gly Gly Ala Ser Leu Asn Leu Ser Leu Thr 800 805 810 Ala GluHis Ser Gly Asn Tyr Ser Cys Glu Ala Asp Asn Gly Leu 815 820 825 Gly AlaGln Arg Ser Glu Thr Val Thr Leu Tyr Ile Thr Gly Leu 830 835 840 Thr AlaAsn Arg Ser Gly Pro Phe Ala Thr Gly Val Ala Gly Gly 845 850 855 Leu LeuSer Ile Ala Gly Leu Ala Ala Gly Ala Leu Leu Leu Tyr 860 865 870 Cys TrpLeu Ser Arg Lys Ala Gly Arg Lys Pro Ala Ser Asp Pro 875 880 885 Ala ArgSer Pro Pro Asp Ser Asp Ser Gln Glu Pro Thr Tyr His 890 895 900 Asn ValPro Ala Trp Glu Glu Leu Gln Pro Val Tyr Thr Asn Ala 905 910 915 Asn ProArg Gly Glu Asn Val Val Tyr Ser Glu Val Arg Ile Ile 920 925 930 Gln GluLys Lys Lys His Ala Val Ala Ser Asp Pro Arg His Leu 935 940 945 Arg AsnLys Gly Ser Pro Ile Ile Tyr Ser Glu Val Lys Val Ala 950 955 960 Ser ThrPro Val Ser Gly Ser Leu Phe Leu Ala Ser Ser Ala Pro 965 970 975 His Arg98 146 PRT Homo Sapien 98 Met Leu Leu Trp Cys Pro Pro Gln Cys Ala CysSer Leu Gly Val 1 5 10 15 Phe Pro Ser Ala Pro Ser Pro Val Trp Gly ThrArg Arg Ser Cys 20 25 30 Glu Pro Ala Thr Arg Val Pro Glu Val Trp Ile LeuSer Pro Leu 35 40 45 Leu Arg His Gly Gly His Thr Gln Thr Gln Asn His ThrAla Ser 50 55 60 Pro Arg Ser Pro Val Met Glu Ser Pro Lys Lys Lys Asn GlnGln 65 70 75 Leu Lys Val Gly Ile Leu His Leu Gly Ser Arg Gln Lys Lys Ile80 85 90 Arg Ile Gln Leu Arg Ser Gln Cys Ala Thr Trp Lys Val Ile Cys 95100 105 Lys Ser Cys Ile Ser Gln Thr Pro Gly Ile Asn Leu Asp Leu Gly 110115 120 Ser Gly Val Lys Val Lys Ile Ile Pro Lys Glu Glu His Cys Lys 125130 135 Met Pro Glu Ala Gly Glu Glu Gln Pro Gln Val 140 145 99 235 PRTHomo Sapien 99 Met Arg Glu Leu Ala Ile Glu Ile Gly Val Arg Ala Leu LeuPhe 1 5 10 15 Gly Val Phe Val Phe Thr Glu Phe Leu Asp Pro Phe Gln ArgVal 20 25 30 Ile Gln Pro Glu Glu Ile Trp Leu Tyr Lys Asn Pro Leu Val Gln35 40 45 Ser Asp Asn Ile Pro Thr Arg Leu Met Phe Ala Ile Ser Phe Leu 5055 60 Thr Pro Leu Ala Val Ile Cys Val Val Lys Ile Ile Arg Arg Thr 65 7075 Asp Lys Thr Glu Ile Lys Glu Ala Phe Leu Ala Val Ser Leu Ala 80 85 90Leu Ala Leu Asn Gly Val Cys Thr Asn Thr Ile Lys Leu Ile Val 95 100 105Gly Arg Pro Arg Ala Asp Phe Phe Tyr Arg Cys Phe Pro Asp Gly 110 115 120Val Met Asn Ser Glu Met His Cys Thr Gly Asp Pro Asp Leu Val 125 130 135Ser Glu Gly Arg Lys Ser Phe Pro Ser Ile His Ser Ser Phe Ala 140 145 150Phe Ser Gly Leu Gly Phe Thr Thr Phe Tyr Leu Ala Gly Lys Leu 155 160 165His Cys Phe Thr Glu Ser Gly Arg Gly Lys Ser Trp Arg Leu Cys 170 175 180Ala Ala Ile Leu Pro Leu Tyr Cys Ala Met Met Ile Ala Leu Ser 185 190 195Arg Met Cys Asp Tyr Lys His His Trp Gln Asp Ser Phe Val Gly 200 205 210Gly Val Ile Ala Leu Ile Phe Ala Tyr Ile Cys Tyr Arg Gln His 215 220 225Tyr Pro Pro Leu Gly Gln His Ser Leu Pro 230 235 100 252 PRT Homo Sapien100 Met Ala Glu Leu Glu Phe Val Gln Ile Ile Ile Ile Val Val Val 1 5 1015 Met Met Val Met Val Val Val Ile Thr Cys Leu Leu Ser His Tyr 20 25 30Lys Leu Ser Ala Arg Ser Phe Ile Ser Arg His Ser Gln Gly Arg 35 40 45 ArgArg Glu Asp Ala Leu Ser Ser Glu Gly Cys Leu Trp Pro Ser 50 55 60 Glu SerThr Val Ser Gly Asn Gly Ile Pro Glu Pro Gln Val Tyr 65 70 75 Ala Pro ProArg Pro Thr Asp Arg Leu Ala Val Pro Pro Phe Ala 80 85 90 Gln Arg Glu ArgPhe His Arg Phe Gln Pro Thr Tyr Pro Tyr Leu 95 100 105 Gln His Glu IleAsp Leu Pro Pro Thr Ile Ser Leu Ser Asp Gly 110 115 120 Glu Glu Pro ProPro Tyr Gln Gly Pro Cys Thr Leu Gln Leu Arg 125 130 135 Asp Pro Glu GlnGln Leu Glu Leu Asn Arg Glu Ser Val Arg Ala 140 145 150 Pro Pro Asn ArgThr Ile Phe Asp Ser Asp Leu Met Asp Ser Ala 155 160 165 Arg Leu Gly GlyPro Cys Pro Pro Ser Ser Asn Ser Gly Ile Ser 170 175 180 Ala Thr Cys TyrGly Ser Gly Gly Arg Met Glu Gly Pro Pro Pro 185 190 195 Thr Tyr Ser GluVal Ile Gly His Tyr Pro Gly Ser Ser Phe Gln 200 205 210 His Gln Gln SerSer Gly Pro Pro Ser Leu Leu Glu Gly Thr Arg 215 220 225 Leu His His ThrHis Ile Ala Pro Leu Glu Ser Ala Ala Ile Trp 230 235 240 Ser Lys Glu LysAsp Lys Gln Lys Gly His Pro Leu 245 250 101 252 PRT Homo Sapien 101 MetAla Glu Leu Glu Phe Val Gln Ile Ile Ile Ile Val Val Val 1 5 10 15 MetMet Val Met Val Val Val Ile Thr Cys Leu Leu Ser His Tyr 20 25 30 Lys LeuSer Ala Arg Ser Phe Ile Ser Arg His Ser Gln Gly Arg 35 40 45 Arg Arg GluAsp Ala Leu Ser Ser Glu Gly Cys Leu Trp Pro Ser 50 55 60 Glu Ser Thr ValSer Gly Asn Gly Ile Pro Glu Pro Gln Val Tyr 65 70 75 Ala Pro Pro Arg ProThr Asp Arg Leu Ala Val Pro Pro Phe Ala 80 85 90 Gln Arg Glu Arg Phe HisArg Phe Gln Pro Thr Tyr Pro Tyr Leu 95 100 105 Gln His Glu Ile Asp LeuPro Pro Thr Ile Ser Leu Ser Asp Gly 110 115 120 Glu Glu Pro Pro Pro TyrGln Gly Pro Cys Thr Leu Gln Leu Arg 125 130 135 Asp Pro Glu Gln Gln LeuGlu Leu Asn Arg Glu Ser Val Arg Ala 140 145 150 Pro Pro Asn Arg Thr IlePhe Asp Ser Asp Leu Met Asp Ser Ala 155 160 165 Arg Leu Gly Gly Pro CysPro Pro Ser Ser Asn Ser Gly Ile Ser 170 175 180 Ala Thr Cys Tyr Gly SerGly Gly Arg Met Glu Gly Pro Pro Pro 185 190 195 Thr Tyr Ser Glu Val IleGly His Tyr Pro Gly Ser Ser Phe Gln 200 205 210 His Gln Gln Ser Ser GlyPro Pro Ser Leu Leu Glu Gly Thr Arg 215 220 225 Leu His His Thr His IleAla Pro Leu Glu Ser Ala Ala Ile Trp 230 235 240 Ser Lys Glu Lys Asp LysGln Lys Gly His Pro Leu 245 250 102 465 PRT Homo Sapien 102 Met Gly GlyAla Val Val Asp Glu Gly Pro Thr Gly Val Lys Ala 1 5 10 15 Pro Asp GlyGly Trp Gly Trp Ala Val Leu Phe Gly Cys Phe Val 20 25 30 Ile Thr Gly PheSer Tyr Ala Phe Pro Lys Ala Val Ser Val Phe 35 40 45 Phe Lys Glu Leu IleGln Glu Phe Gly Ile Gly Tyr Ser Asp Thr 50 55 60 Ala Trp Ile Ser Ser IleLeu Leu Ala Met Leu Tyr Gly Thr Gly 65 70 75 Pro Leu Cys Ser Val Cys ValAsn Arg Phe Gly Cys Arg Pro Val 80 85 90 Met Leu Val Gly Gly Leu Phe AlaSer Leu Gly Met Val Ala Ala 95 100 105 Ser Phe Cys Arg Ser Ile Ile GlnVal Tyr Leu Thr Thr Gly Val 110 115 120 Ile Thr Gly Leu Gly Leu Ala LeuAsn Phe Gln Pro Ser Leu Ile 125 130 135 Met Leu Asn Arg Tyr Phe Ser LysArg Arg Pro Met Ala Asn Gly 140 145 150 Leu Ala Ala Ala Gly Ser Pro ValPhe Leu Cys Ala Leu Ser Pro 155 160 165 Leu Gly Gln Leu Leu Gln Asp ArgTyr Gly Trp Arg Gly Gly Phe 170 175 180 Leu Ile Leu Gly Gly Leu Leu LeuAsn Cys Cys Val Cys Ala Ala 185 190 195 Leu Met Arg Pro Leu Val Val ThrAla Gln Pro Gly Ser Gly Pro 200 205 210 Pro Arg Pro Ser Arg Arg Leu LeuAsp Leu Ser Val Phe Arg Asp 215 220 225 Arg Gly Phe Val Leu Tyr Ala ValAla Ala Ser Val Met Val Leu 230 235 240 Gly Leu Phe Val Pro Pro Val PheVal Val Ser Tyr Ala Lys Asp 245 250 255 Leu Gly Val Pro Asp Thr Lys AlaAla Phe Leu Leu Thr Ile Leu 260 265 270 Gly Phe Ile Asp Ile Phe Ala ArgPro Ala Ala Gly Phe Val Ala 275 280 285 Gly Leu Gly Lys Val Arg Pro TyrSer Val Tyr Leu Phe Ser Phe 290 295 300 Ser Met Phe Phe Asn Gly Leu AlaAsp Leu Ala Gly Ser Thr Ala 305 310 315 Gly Asp Tyr Gly Gly Leu Val ValPhe Cys Ile Phe Phe Gly Ile 320 325 330 Ser Tyr Gly Met Val Gly Ala LeuGln Phe Glu Val Leu Met Ala 335 340 345 Ile Val Gly Thr His Lys Phe SerSer Ala Ile Gly Leu Val Leu 350 355 360 Leu Met Glu Ala Val Ala Val LeuVal Gly Pro Pro Ser Gly Gly 365 370 375 Lys Leu Leu Asp Ala Thr His ValTyr Met Tyr Val Phe Ile Leu 380 385 390 Ala Gly Ala Glu Val Leu Thr SerSer Leu Ile Leu Leu Leu Gly 395 400 405 Asn Phe Phe Cys Ile Arg Lys LysPro Lys Glu Pro Gln Pro Glu 410 415 420 Val Ala Ala Ala Glu Glu Glu LysLeu His Lys Pro Pro Ala Asp 425 430 435 Ser Gly Val Asp Leu Arg Glu ValGlu His Phe Leu Lys Ala Glu 440 445 450 Pro Glu Lys Asn Gly Glu Val ValHis Thr Pro Glu Thr Ser Val 455 460 465 103 445 PRT Homo Sapien 103 MetAla Ala Pro Thr Pro Ala Arg Pro Val Leu Thr His Leu Leu 1 5 10 15 ValAla Leu Phe Gly Met Gly Ser Trp Ala Ala Val Asn Gly Ile 20 25 30 Trp ValGlu Leu Pro Val Val Val Lys Glu Leu Pro Glu Gly Trp 35 40 45 Ser Leu ProSer Tyr Val Ser Val Leu Val Ala Leu Gly Asn Leu 50 55 60 Gly Leu Leu ValVal Thr Leu Trp Arg Arg Leu Ala Pro Gly Lys 65 70 75 Asp Glu Gln Val ProIle Arg Val Val Gln Val Leu Gly Met Val 80 85 90 Gly Thr Ala Leu Leu AlaSer Leu Trp His His Val Ala Pro Val 95 100 105 Ala Gly Gln Leu His SerVal Ala Phe Leu Ala Leu Ala Phe Val 110 115 120 Leu Ala Leu Ala Cys CysAla Ser Asn Val Thr Phe Leu Pro Phe 125 130 135 Leu Ser His Leu Pro ProArg Phe Leu Arg Ser Phe Phe Leu Gly 140 145 150 Gln Gly Leu Ser Ala LeuLeu Pro Cys Val Leu Ala Leu Val Gln 155 160 165 Gly Val Gly Arg Leu GluCys Pro Pro Ala Pro Ile Asn Gly Thr 170 175 180 Pro Gly Pro Pro Leu AspPhe Leu Glu Arg Phe Pro Ala Ser Thr 185 190 195 Phe Phe Trp Ala Leu ThrAla Leu Leu Val Ala Ser Ala Ala Ala 200 205 210 Phe Gln Gly Leu Leu LeuLeu Leu Pro Pro Pro Pro Ser Val Pro 215 220 225 Thr Gly Glu Leu Gly SerGly Leu Gln Val Gly Ala Pro Gly Ala 230 235 240 Glu Glu Glu Val Glu GluSer Ser Pro Leu Gln Glu Pro Pro Ser 245 250 255 Gln Ala Ala Gly Thr ThrPro Gly Pro Asp Pro Lys Ala Tyr Gln 260 265 270 Leu Leu Ser Ala Arg SerAla Cys Leu Leu Gly Leu Leu Ala Ala 275 280 285 Thr Asn Ala Leu Thr AsnGly Val Leu Pro Ala Val Gln Ser Phe 290 295 300 Ser Cys Leu Pro Tyr GlyArg Leu Ala Tyr His Leu Ala Val Val 305 310 315 Leu Gly Ser Ala Ala AsnPro Leu Ala Cys Phe Leu Ala Met Gly 320 325 330 Val Leu Cys Arg Ser LeuAla Gly Leu Gly Gly Leu Ser Leu Leu 335 340 345 Gly Val Phe Cys Gly GlyTyr Leu Met Ala Leu Ala Val Leu Ser 350 355 360 Pro Cys Pro Pro Leu ValGly Thr Ser Ala Gly Val Val Leu Val 365 370 375 Val Leu Ser Trp Val LeuCys Leu Gly Val Phe Ser Tyr Val Lys 380 385 390 Val Ala Ala Ser Ser LeuLeu His Gly Gly Gly Arg Pro Ala Leu 395 400 405 Leu Ala Ala Gly Val AlaIle Gln Val Gly Ser Leu Leu Gly Ala 410 415 420 Val Ala Met Phe Pro ProThr Ser Ile Tyr His Val Phe His Ser 425 430 435 Arg Lys Asp Cys Ala AspPro Cys Asp Ser 440 445 104 398 PRT Homo Sapien 104 Met His Thr Val AlaThr Ser Gly Pro Asn Ala Ser Trp Gly Ala 1 5 10 15 Pro Ala Asn Ala SerGly Cys Pro Gly Cys Gly Ala Asn Ala Ser 20 25 30 Asp Gly Pro Val Pro SerPro Arg Ala Val Asp Ala Trp Leu Val 35 40 45 Pro Leu Phe Phe Ala Ala LeuMet Leu Leu Gly Leu Val Gly Asn 50 55 60 Ser Leu Val Ile Tyr Val Ile CysArg His Lys Pro Met Arg Thr 65 70 75 Val Thr Asn Phe Tyr Ile Ala Asn LeuAla Ala Thr Asp Val Thr 80 85 90 Phe Leu Leu Cys Cys Val Pro Phe Thr AlaLeu Leu Tyr Pro Leu 95 100 105 Pro Gly Trp Val Leu Gly Asp Phe Met CysLys Phe Val Asn Tyr 110 115 120 Ile Gln Gln Val Ser Val Gln Ala Thr CysAla Thr Leu Thr Ala 125 130 135 Met Ser Val Asp Arg Trp Tyr Val Thr ValPhe Pro Leu Arg Ala 140 145 150 Leu His Arg Arg Thr Pro Arg Leu Ala LeuAla Val Ser Leu Ser 155 160 165 Ile Trp Val Gly Ser Ala Ala Val Ser AlaPro Val Leu Ala Leu 170 175 180 His Arg Leu Ser Pro Gly Pro Arg Ala TyrCys Ser Glu Ala Phe 185 190 195 Pro Ser Arg Ala Leu Glu Arg Ala Phe AlaLeu Tyr Asn Leu Leu 200 205 210 Ala Leu Tyr Leu Leu Pro Leu Leu Ala ThrCys Ala Cys Tyr Ala 215 220 225 Ala Met Leu Arg His Leu Gly Arg Val AlaVal Arg Pro Ala Pro 230 235 240 Ala Asp Ser Ala Leu Gln Gly Gln Val LeuAla Glu Arg Ala Gly 245 250 255 Ala Val Arg Ala Lys Val Ser Arg Leu ValAla Ala Val Val Leu 260 265 270 Leu Phe Ala Ala Cys Trp Gly Pro Ile GlnLeu Phe Leu Val Leu 275 280 285 Gln Ala Leu Gly Pro Ala Gly Ser Trp HisPro Arg Ser Tyr Ala 290 295 300 Ala Tyr Ala Leu Lys Thr Trp Ala His CysMet Ser Tyr Ser Asn 305 310 315 Ser Ala Leu Asn Pro Leu Leu Tyr Ala PheLeu Gly Ser His Phe 320 325 330 Arg Gln Ala Phe Arg Arg Val Cys Pro CysAla Pro Arg Arg Pro 335 340 345 Arg Arg Pro Arg Arg Pro Gly Pro Ser AspPro Ala Ala Pro His 350 355 360 Ala Glu Leu His Arg Leu Gly Ser His ProAla Pro Ala Arg Ala 365 370 375 Gln Lys Pro Gly Ser Ser Gly Leu Ala AlaArg Gly Leu Cys Val 380 385 390 Leu Gly Glu Asp Asn Ala Pro Leu 395 105359 PRT Homo Sapien 105 Met Ser Met Asn Asn Ser Lys Gln Leu Val Ser ProAla Ala Ala 1 5 10 15 Leu Leu Ser Asn Thr Thr Cys Gln Thr Glu Asn ArgLeu Ser Val 20 25 30 Phe Phe Ser Val Ile Phe Met Thr Val Gly Ile Leu SerAsn Ser 35 40 45 Leu Ala Ile Ala Ile Leu Met Lys Ala Tyr Gln Arg Phe ArgGln 50 55 60 Lys Ser Lys Ala Ser Phe Leu Leu Leu Ala Ser Gly Leu Val Ile65 70 75 Thr Asp Phe Phe Gly His Leu Ile Asn Gly Ala Ile Ala Val Phe 8085 90 Val Tyr Ala Ser Asp Lys Glu Trp Ile Arg Phe Asp Gln Ser Asn 95 100105 Val Leu Cys Ser Ile Phe Gly Ile Cys Met Val Phe Ser Gly Leu 110 115120 Cys Pro Leu Leu Leu Gly Ser Val Met Ala Ile Glu Arg Cys Ile 125 130135 Gly Val Thr Lys Pro Ile Phe His Ser Thr Lys Ile Thr Ser Lys 140 145150 His Val Lys Met Met Leu Ser Gly Val Cys Leu Phe Ala Val Phe 155 160165 Ile Ala Leu Leu Pro Ile Leu Gly His Arg Asp Tyr Lys Ile Gln 170 175180 Ala Ser Arg Thr Trp Cys Phe Tyr Asn Thr Glu Asp Ile Lys Asp 185 190195 Trp Glu Asp Arg Phe Tyr Leu Leu Leu Phe Ser Phe Leu Gly Leu 200 205210 Leu Ala Leu Gly Val Ser Leu Leu Cys Asn Ala Ile Thr Gly Ile 215 220225 Thr Leu Leu Arg Val Lys Phe Lys Ser Gln Gln His Arg Gln Gly 230 235240 Arg Ser His His Leu Glu Met Val Ile Gln Leu Leu Ala Ile Met 245 250255 Cys Val Ser Cys Ile Cys Trp Ser Pro Phe Leu Val Thr Met Ala 260 265270 Asn Ile Gly Ile Asn Gly Asn His Ser Leu Glu Thr Cys Glu Thr 275 280285 Thr Leu Phe Ala Leu Arg Met Ala Thr Trp Asn Gln Ile Leu Asp 290 295300 Pro Trp Val Tyr Ile Leu Leu Arg Lys Ala Val Leu Lys Asn Leu 305 310315 Tyr Lys Leu Ala Ser Gln Cys Cys Gly Val His Val Ile Ser Leu 320 325330 His Ile Trp Glu Leu Ser Ser Ile Lys Asn Ser Leu Lys Val Ala 335 340345 Ala Ile Ser Glu Ser Pro Val Ala Glu Lys Ser Ala Ser Thr 350 355 106819 PRT Homo Sapien 106 Met Ser Arg Met Ser Arg His Pro Asp Lys Asp LeuAla Gln Gly 1 5 10 15 Pro Phe Asn Thr Cys Cys Gly Cys Thr Leu Met AlaSer Pro Ala 20 25 30 Asn Leu Pro Pro Asn Thr Gln Ala Ala Ala Glu Arg AlaLeu Ser 35 40 45 Gln Ser Arg Trp Lys Arg Val Gln Val Pro Ala Pro Ala SerLeu 50 55 60 Ser Pro Phe Pro Leu Ala Met Ala Ser Val Ala Phe Trp Ile Ser65 70 75 Ile Leu Ile Gly Cys Glu Glu Gln Thr Leu Cys Arg Gly Trp Arg 8085 90 Ser Pro Val Gly Asp Gly Cys Ala His Val Pro Pro Gln Glu Arg 95 100105 Ala Thr Ala Glu Ala Asp Pro Pro Gly Arg Cys Ser Thr Ser Thr 110 115120 Ala Ser Ser Thr Ile Cys Gly Leu Trp His Leu Ser Pro Arg Leu 125 130135 Gln Leu Leu Pro Pro Leu His Ser Arg Gln Gly Glu Glu Ser Gly 140 145150 Lys Thr Glu Lys Val Leu Leu Trp Gly Arg Glu Gly Leu His Val 155 160165 Trp Lys Pro Gly Val Leu Gln Pro Asp Val His Gly Thr Ser Asn 170 175180 Leu Gly Asn Cys Ser Phe Leu His Gly Leu Val Thr Ala Pro Ser 185 190195 Cys Pro Arg Arg Ala Gly Ala Glu Leu Leu Asn Ser Leu Gly Ser 200 205210 Gln Phe Ala Ile Ser Leu Phe Glu Val Gln Ser Gly Thr Glu Pro 215 220225 Ser Ile Thr Gly Val Ala Thr Ser Gly Gln Cys Arg Ala Met Pro 230 235240 Leu Lys His Tyr Leu Leu Leu Leu Val Gly Cys Gln Ala Trp Gly 245 250255 Ala Gly Leu Ala Tyr His Gly Cys Pro Ser Glu Cys Thr Cys Ser 260 265270 Arg Ala Ser Gln Val Glu Cys Thr Gly Ala Arg Ile Val Ala Val 275 280285 Pro Thr Pro Leu Pro Trp Asn Ala Met Ser Leu Gln Ile Leu Asn 290 295300 Thr His Ile Thr Glu Leu Asn Glu Ser Pro Phe Leu Asn Ile Ser 305 310315 Ala Leu Ile Ala Leu Arg Ile Glu Lys Asn Glu Leu Ser Arg Ile 320 325330 Thr Pro Gly Ala Phe Arg Asn Leu Gly Ser Leu Arg Tyr Leu Ser 335 340345 Leu Ala Asn Asn Lys Leu Gln Val Leu Pro Ile Gly Leu Phe Gln 350 355360 Gly Leu Asp Ser Leu Glu Ser Leu Leu Leu Ser Ser Asn Gln Leu 365 370375 Leu Gln Ile Gln Pro Ala His Phe Ser Gln Cys Ser Asn Leu Lys 380 385390 Glu Leu Gln Leu His Gly Asn His Leu Glu Tyr Ile Pro Asp Gly 395 400405 Ala Phe Asp His Leu Val Gly Leu Thr Lys Leu Asn Leu Gly Lys 410 415420 Asn Ser Leu Thr His Ile Ser Pro Arg Val Phe Gln His Leu Gly 425 430435 Asn Leu Gln Val Leu Arg Leu Tyr Glu Asn Arg Leu Thr Asp Ile 440 445450 Pro Met Gly Thr Phe Asp Gly Leu Val Asn Leu Gln Glu Leu Ala 455 460465 Leu Gln Gln Asn Gln Ile Gly Leu Leu Ser Pro Gly Leu Phe His 470 475480 Asn Asn His Asn Leu Gln Arg Leu Tyr Leu Ser Asn Asn His Ile 485 490495 Ser Gln Leu Pro Pro Ser Ile Phe Met Gln Leu Pro Gln Leu Asn 500 505510 Arg Leu Thr Leu Phe Gly Asn Ser Leu Lys Glu Leu Ser Leu Gly 515 520525 Ile Phe Gly Pro Met Pro Asn Leu Arg Glu Leu Trp Leu Tyr Asp 530 535540 Asn His Ile Ser Ser Leu Pro Asp Asn Val Phe Ser Asn Leu Arg 545 550555 Gln Leu Gln Val Leu Ile Leu Ser Arg Asn Gln Ile Ser Phe Ile 560 565570 Ser Pro Gly Ala Phe Asn Gly Leu Thr Glu Leu Arg Glu Leu Ser 575 580585 Leu His Thr Asn Ala Leu Gln Asp Leu Asp Gly Asn Val Phe Arg 590 595600 Met Leu Ala Asn Leu Gln Asn Ile Ser Leu Gln Asn Asn Arg Leu 605 610615 Arg Gln Leu Pro Gly Asn Ile Phe Ala Asn Val Asn Gly Leu Met 620 625630 Ala Ile Gln Leu Gln Asn Asn Gln Leu Glu Asn Leu Pro Leu Gly 635 640645 Ile Phe Asp His Leu Gly Lys Leu Cys Glu Leu Arg Leu Tyr Asp 650 655660 Asn Pro Trp Arg Cys Asp Ser Asp Ile Leu Pro Leu Arg Asn Trp 665 670675 Leu Leu Leu Asn Gln Pro Arg Leu Gly Thr Asp Thr Val Pro Val 680 685690 Cys Phe Ser Pro Ala Asn Val Arg Gly Gln Ser Leu Ile Ile Ile 695 700705 Asn Val Asn Val Ala Val Pro Ser Val His Val Pro Glu Val Pro 710 715720 Ser Tyr Pro Glu Thr Pro Trp Tyr Pro Asp Thr Pro Ser Tyr Pro 725 730735 Asp Thr Thr Ser Val Ser Ser Thr Thr Glu Leu Thr Ser Pro Val 740 745750 Glu Asp Tyr Thr Asp Leu Thr Thr Ile Gln Val Thr Asp Asp Arg 755 760765 Ser Val Trp Gly Met Thr His Ala His Ser Gly Leu Ala Ile Ala 770 775780 Ala Ile Val Ile Gly Ile Val Ala Leu Ala Cys Ser Leu Ala Ala 785 790795 Cys Val Gly Cys Cys Cys Cys Lys Lys Arg Ser Gln Ala Val Leu 800 805810 Met Gln Met Lys Ala Pro Asn Glu Cys 815 107 3014 PRT Homo Sapien 107Met Ala Pro Pro Pro Pro Pro Val Leu Pro Val Leu Leu Leu Leu 1 5 10 15Ala Ala Ala Ala Ala Leu Pro Ala Met Gly Leu Arg Ala Ala Ala 20 25 30 TrpGlu Pro Arg Val Pro Gly Gly Thr Arg Ala Phe Ala Leu Arg 35 40 45 Pro GlyCys Thr Tyr Ala Val Gly Ala Ala Cys Thr Pro Arg Ala 50 55 60 Pro Arg GluLeu Leu Asp Val Gly Arg Asp Gly Arg Leu Ala Gly 65 70 75 Arg Arg Arg ValSer Gly Ala Gly Arg Pro Leu Pro Leu Gln Val 80 85 90 Arg Leu Val Ala ArgSer Ala Pro Thr Ala Leu Ser Arg Arg Leu 95 100 105 Arg Ala Arg Thr HisLeu Pro Gly Cys Gly Ala Arg Ala Arg Leu 110 115 120 Cys Gly Thr Gly AlaArg Leu Cys Gly Ala Leu Cys Phe Pro Val 125 130 135 Pro Gly Gly Cys AlaAla Ala Gln His Ser Ala Leu Ala Ala Pro 140 145 150 Thr Thr Leu Pro AlaCys Arg Cys Pro Pro Arg Pro Arg Pro Arg 155 160 165 Cys Pro Gly Arg ProIle Cys Leu Pro Pro Gly Gly Ser Val Arg 170 175 180 Leu Arg Leu Leu CysAla Leu Arg Arg Ala Ala Gly Ala Val Arg 185 190 195 Val Gly Leu Ala LeuGlu Ala Ala Thr Ala Gly Thr Pro Ser Ala 200 205 210 Ser Pro Ser Pro SerPro Pro Leu Pro Pro Asn Leu Pro Glu Ala 215 220 225 Arg Ala Gly Pro AlaArg Arg Ala Arg Arg Gly Thr Ser Gly Arg 230 235 240 Gly Ser Leu Lys PhePro Met Pro Asn Tyr Gln Val Ala Leu Phe 245 250 255 Glu Asn Glu Pro AlaGly Thr Leu Ile Leu Gln Leu His Ala His 260 265 270 Tyr Thr Ile Glu GlyGlu Glu Glu Arg Val Ser Tyr Tyr Met Glu 275 280 285 Gly Leu Phe Asp GluArg Ser Arg Gly Tyr Phe Arg Ile Asp Ser 290 295 300 Ala Thr Gly Ala ValSer Thr Asp Ser Val Leu Asp Arg Glu Thr 305 310 315 Lys Glu Thr His ValLeu Arg Val Lys Ala Val Asp Tyr Ser Thr 320 325 330 Pro Pro Arg Ser AlaThr Thr Tyr Ile Thr Val Leu Val Lys Asp 335 340 345 Thr Asn Asp His SerPro Val Phe Glu Gln Ser Glu Tyr Arg Glu 350 355 360 Arg Val Arg Glu AsnLeu Glu Val Gly Tyr Glu Val Leu Thr Ile 365 370 375 Arg Ala Ser Asp ArgAsp Ser Pro Ile Asn Ala Asn Leu Arg Tyr 380 385 390 Arg Val Leu Gly GlyAla Trp Asp Val Phe Gln Leu Asn Glu Ser 395 400 405 Ser Gly Val Val SerThr Arg Ala Val Leu Asp Arg Glu Glu Ala 410 415 420 Ala Glu Tyr Gln LeuLeu Val Glu Ala Asn Asp Gln Gly Arg Asn 425 430 435 Pro Gly Pro Leu SerAla Thr Ala Thr Val Tyr Ile Glu Val Glu 440 445 450 Asp Glu Asn Asp AsnTyr Pro Gln Phe Ser Glu Gln Asn Tyr Val 455 460 465 Val Gln Val Pro GluAsp Val Gly Leu Asn Thr Ala Val Leu Arg 470 475 480 Val Gln Ala Thr AspArg Asp Gln Gly Gln Asn Ala Ala Ile His 485 490 495 Tyr Ser Ile Leu SerGly Asn Val Ala Gly Gln Phe Tyr Leu His 500 505 510 Ser Leu Ser Gly IleLeu Asp Val Ile Asn Pro Leu Asp Phe Glu 515 520 525 Asp Val Gln Lys TyrSer Leu Ser Ile Lys Ala Gln Asp Gly Gly 530 535 540 Arg Pro Pro Leu IleAsn Ser Ser Gly Val Val Ser Val Gln Val 545 550 555 Leu Asp Val Asn AspAsn Glu Pro Ile Phe Val Ser Ser Pro Phe 560 565 570 Gln Ala Thr Val LeuGlu Asn Val Pro Leu Gly Tyr Pro Val Val 575 580 585 His Ile Gln Ala ValAsp Ala Asp Ser Gly Glu Asn Ala Arg Leu 590 595 600 His Tyr Arg Leu ValAsp Thr Ala Ser Thr Phe Leu Gly Gly Gly 605 610 615 Ser Ala Gly Pro LysAsn Pro Ala Pro Thr Pro Asp Phe Pro Phe 620 625 630 Gln Ile His Asn SerSer Gly Trp Ile Thr Val Cys Ala Glu Leu 635 640 645 Asp Arg Glu Glu ValGlu His Tyr Ser Phe Gly Val Glu Ala Val 650 655 660 Asp His Gly Ser ProPro Met Ser Ser Ser Thr Ser Val Ser Ile 665 670 675 Thr Val Leu Asp ValAsn Asp Asn Asp Pro Val Phe Thr Gln Pro 680 685 690 Thr Tyr Glu Leu ArgLeu Asn Glu Asp Ala Ala Val Gly Ser Ser 695 700 705 Val Leu Thr Leu GlnAla Arg Asp Arg Asp Ala Asn Ser Val Ile 710 715 720 Thr Tyr Gln Leu ThrGly Gly Asn Thr Arg Asn Arg Phe Ala Leu 725 730 735 Ser Ser Gln Arg GlyGly Gly Leu Ile Thr Leu Ala Leu Pro Leu 740 745 750 Asp Tyr Lys Gln GluGln Gln Tyr Val Leu Ala Val Thr Ala Ser 755 760 765 Asp Gly Thr Arg SerHis Thr Ala His Val Leu Ile Asn Val Thr 770 775 780 Asp Ala Asn Thr HisArg Pro Val Phe Gln Ser Ser His Tyr Thr 785 790 795 Val Ser Val Ser GluAsp Arg Pro Val Gly Thr Ser Ile Ala Thr 800 805 810 Leu Ser Ala Asn AspGlu Asp Thr Gly Glu Asn Ala Arg Ile Thr 815 820 825 Tyr Val Ile Gln AspPro Val Pro Gln Phe Arg Ile Asp Pro Asp 830 835 840 Ser Gly Thr Met TyrThr Met Met Glu Leu Asp Tyr Glu Asn Gln 845 850 855 Val Ala Tyr Thr LeuThr Ile Met Ala Gln Asp Asn Gly Ile Pro 860 865 870 Gln Lys Ser Asp ThrThr Thr Leu Glu Ile Leu Ile Leu Asp Ala 875 880 885 Asn Asp Asn Ala ProGln Phe Leu Trp Asp Phe Tyr Gln Gly Ser 890 895 900 Ile Phe Glu Asp AlaPro Pro Ser Thr Ser Ile Leu Gln Val Ser 905 910 915 Ala Thr Asp Arg AspSer Gly Pro Asn Gly Arg Leu Leu Tyr Thr 920 925 930 Phe Gln Gly Gly AspAsp Gly Asp Gly Asp Phe Tyr Ile Glu Pro 935 940 945 Thr Ser Gly Val IleArg Thr Gln Arg Arg Leu Asp Arg Glu Asn 950 955 960 Val Ala Val Tyr AsnLeu Trp Ala Leu Ala Val Asp Arg Gly Ser 965 970 975 Pro Thr Pro Leu SerAla Ser Val Glu Ile Gln Val Thr Ile Leu 980 985 990 Asp Ile Asn Asp AsnAla Pro Met Phe Glu Lys Asp Glu Leu Glu 995 1000 1005 Leu Phe Val GluGlu Asn Asn Pro Val Gly Ser Val Val Ala Lys 1010 1015 1020 Ile Arg AlaAsn Asp Pro Asp Glu Gly Pro Asn Ala Gln Ile Met 1025 1030 1035 Tyr GlnIle Val Glu Gly Asp Met Arg His Phe Phe Gln Leu Asp 1040 1045 1050 LeuLeu Asn Gly Asp Leu Arg Ala Met Val Glu Leu Asp Phe Glu 1055 1060 1065Val Arg Arg Glu Tyr Val Leu Val Val Gln Ala Thr Ser Ala Pro 1070 10751080 Leu Val Ser Arg Ala Thr Val His Ile Leu Leu Val Asp Gln Asn 10851090 1095 Asp Asn Pro Pro Val Leu Pro Asp Phe Gln Ile Leu Phe Asn Asn1100 1105 1110 Tyr Val Thr Asn Lys Ser Asn Ser Phe Pro Thr Gly Val IleGly 1115 1120 1125 Cys Ile Pro Ala His Asp Pro Asp Val Ser Asp Ser LeuAsn Tyr 1130 1135 1140 Thr Phe Val Gln Gly Asn Glu Leu Arg Leu Leu LeuLeu Asp Pro 1145 1150 1155 Ala Thr Gly Glu Leu Gln Leu Ser Arg Asp LeuAsp Asn Asn Arg 1160 1165 1170 Pro Leu Glu Ala Leu Met Glu Val Ser ValSer Asp Gly Ile His 1175 1180 1185 Ser Val Thr Ala Phe Cys Thr Leu ArgVal Thr Ile Ile Thr Asp 1190 1195 1200 Asp Met Leu Thr Asn Ser Ile ThrVal Arg Leu Glu Asn Met Ser 1205 1210 1215 Gln Glu Lys Phe Leu Ser ProLeu Leu Ala Leu Phe Val Glu Gly 1220 1225 1230 Val Ala Ala Val Leu SerThr Thr Lys Asp Asp Val Phe Val Phe 1235 1240 1245 Asn Val Gln Asn AspThr Asp Val Ser Ser Asn Ile Leu Asn Val 1250 1255 1260 Thr Phe Ser AlaLeu Leu Pro Gly Gly Val Arg Gly Gln Phe Phe 1265 1270 1275 Pro Ser GluAsp Leu Gln Glu Gln Ile Tyr Leu Asn Arg Thr Leu 1280 1285 1290 Leu ThrThr Ile Ser Thr Gln Arg Val Leu Pro Phe Asp Asp Asn 1295 1300 1305 IleCys Leu Arg Glu Pro Cys Glu Asn Tyr Met Lys Cys Val Ser 1310 1315 1320Val Leu Arg Phe Asp Ser Ser Ala Pro Phe Leu Ser Ser Thr Thr 1325 13301335 Val Leu Phe Arg Pro Ile His Pro Ile Asn Gly Leu Arg Cys Arg 13401345 1350 Cys Pro Pro Gly Phe Thr Gly Asp Tyr Cys Glu Thr Glu Ile Asp1355 1360 1365 Leu Cys Tyr Ser Asp Pro Cys Gly Ala Asn Gly Arg Cys ArgSer 1370 1375 1380 Arg Glu Gly Gly Tyr Thr Cys Glu Cys Phe Glu Asp PheThr Gly 1385 1390 1395 Glu His Cys Glu Val Asp Ala Arg Ser Gly Arg CysAla Asn Gly 1400 1405 1410 Val Cys Lys Asn Gly Gly Thr Cys Val Asn LeuLeu Ile Gly Gly 1415 1420 1425 Phe His Cys Val Cys Pro Pro Gly Glu TyrGlu Arg Pro Tyr Cys 1430 1435 1440 Glu Val Thr Thr Arg Ser Phe Pro ProGln Ser Phe Val Thr Phe 1445 1450 1455 Arg Gly Leu Arg Gln Arg Phe HisPhe Thr Ile Ser Leu Thr Phe 1460 1465 1470 Ala Thr Gln Glu Arg Asn GlyLeu Leu Leu Tyr Asn Gly Arg Phe 1475 1480 1485 Asn Glu Lys His Asp PheIle Ala Leu Glu Ile Val Asp Glu Gln 1490 1495 1500 Val Gln Leu Thr PheSer Ala Gly Glu Thr Thr Thr Thr Val Ala 1505 1510 1515 Pro Lys Val ProSer Gly Val Ser Asp Gly Arg Trp His Ser Val 1520 1525 1530 Gln Val GlnTyr Tyr Asn Lys Pro Asn Ile Gly His Leu Gly Leu 1535 1540 1545 Pro HisGly Pro Ser Gly Glu Lys Met Ala Val Val Thr Val Asp 1550 1555 1560 AspCys Asp Thr Thr Met Ala Val Arg Phe Gly Lys Asp Ile Gly 1565 1570 1575Asn Tyr Ser Cys Ala Ala Gln Gly Thr Gln Thr Gly Ser Lys Lys 1580 15851590 Ser Leu Asp Leu Thr Gly Pro Leu Leu Leu Gly Gly Val Pro Asn 15951600 1605 Leu Pro Glu Asp Phe Pro Val His Asn Arg Gln Phe Val Gly Cys1610 1615 1620 Met Arg Asn Leu Ser Val Asp Gly Lys Asn Val Asp Met AlaGly 1625 1630 1635 Phe Ile Ala Asn Asn Gly Thr Arg Glu Gly Cys Ala AlaArg Arg 1640 1645 1650 Asn Phe Cys Asp Gly Arg Arg Cys Gln Asn Gly GlyThr Cys Val 1655 1660 1665 Asn Arg Trp Asn Met Tyr Leu Cys Glu Cys ProLeu Arg Phe Gly 1670 1675 1680 Gly Lys Asn Cys Glu Gln Ala Met Pro HisPro Gln Leu Phe Ser 1685 1690 1695 Gly Glu Ser Val Val Ser Trp Ser AspLeu Asn Ile Ile Ile Ser 1700 1705 1710 Val Pro Trp Tyr Leu Gly Leu MetPhe Arg Thr Arg Lys Glu Asp 1715 1720 1725 Ser Val Leu Met Glu Ala ThrSer Gly Gly Pro Thr Ser Phe Arg 1730 1735 1740 Leu Gln Ile Leu Asn AsnTyr Leu Gln Phe Glu Val Ser His Gly 1745 1750 1755 Pro Ser Asp Val GluSer Val Met Leu Ser Gly Leu Arg Val Thr 1760 1765 1770 Asp Gly Glu TrpHis His Leu Leu Ile Glu Leu Lys Asn Val Lys 1775 1780 1785 Glu Asp SerGlu Met Lys His Leu Val Thr Met Thr Leu Asp Tyr 1790 1795 1800 Gly MetAsp Gln Asn Lys Ala Asp Ile Gly Gly Met Leu Pro Gly 1805 1810 1815 LeuThr Val Arg Ser Val Val Val Gly Gly Ala Ser Glu Asp Lys 1820 1825 1830Val Ser Val Arg Arg Gly Phe Arg Gly Cys Met Gln Gly Val Arg 1835 18401845 Met Gly Gly Thr Pro Thr Asn Val Ala Thr Leu Asn Met Asn Asn 18501855 1860 Ala Leu Lys Val Arg Val Lys Asp Gly Cys Asp Val Asp Asp Pro1865 1870 1875 Cys Thr Ser Ser Pro Cys Pro Pro Asn Ser Arg Cys His AspAla 1880 1885 1890 Trp Glu Asp Tyr Ser Cys Val Cys Asp Lys Gly Tyr LeuGly Ile 1895 1900 1905 Asn Cys Val Asp Ala Cys His Leu Asn Pro Cys GluAsn Met Gly 1910 1915 1920 Ala Cys Val Arg Ser Pro Gly Ser Pro Gln GlyTyr Val Cys Glu 1925 1930 1935 Cys Gly Pro Ser His Tyr Gly Pro Tyr CysGlu Asn Lys Leu Asp 1940 1945 1950 Leu Pro Cys Pro Arg Gly Trp Trp GlyAsn Pro Val Cys Gly Pro 1955 1960 1965 Cys His Cys Ala Val Ser Lys GlyPhe Asp Pro Asp Cys Asn Lys 1970 1975 1980 Thr Asn Gly Gln Cys Gln CysLys Glu Asn Tyr Tyr Lys Leu Leu 1985 1990 1995 Ala Gln Asp Thr Cys LeuPro Cys Asp Cys Phe Pro His Gly Ser 2000 2005 2010 His Ser Arg Thr CysAsp Met Ala Thr Gly Gln Cys Ala Cys Lys 2015 2020 2025 Pro Gly Val IleGly Arg Gln Cys Asn Arg Cys Asp Asn Pro Phe 2030 2035 2040 Ala Glu ValThr Thr Leu Gly Cys Glu Val Ile Tyr Asn Gly Cys 2045 2050 2055 Pro LysAla Phe Glu Ala Gly Ile Trp Trp Pro Gln Thr Lys Phe 2060 2065 2070 GlyGln Pro Ala Ala Val Pro Cys Pro Lys Gly Ser Val Gly Asn 2075 2080 2085Ala Val Arg His Cys Ser Gly Glu Lys Gly Trp Leu Pro Pro Glu 2090 20952100 Leu Phe Asn Cys Thr Thr Ile Ser Phe Val Asp Leu Arg Ala Met 21052110 2115 Asn Glu Lys Leu Ser Arg Asn Glu Thr Gln Val Asp Gly Ala Arg2120 2125 2130 Ala Leu Gln Leu Val Arg Ala Leu Arg Ser Ala Thr Gln HisThr 2135 2140 2145 Gly Thr Leu Phe Gly Asn Asp Val Arg Thr Ala Tyr GlnLeu Leu 2150 2155 2160 Gly His Val Leu Gln His Glu Ser Trp Gln Gln GlyPhe Asp Leu 2165 2170 2175 Ala Ala Thr Gln Asp Ala Asp Phe His Glu AspVal Ile His Ser 2180 2185 2190 Gly Ser Ala Leu Leu Ala Pro Ala Thr ArgAla Ala Trp Glu Gln 2195 2200 2205 Ile Gln Arg Ser Glu Gly Gly Thr AlaGln Leu Leu Arg Arg Leu 2210 2215 2220 Glu Gly Tyr Phe Ser Asn Val AlaArg Asn Val Arg Arg Thr Tyr 2225 2230 2235 Leu Arg Pro Phe Val Ile ValThr Ala Asn Met Ile Leu Ala Val 2240 2245 2250 Asp Ile Phe Asp Lys PheAsn Phe Thr Gly Ala Arg Val Pro Arg 2255 2260 2265 Phe Asp Thr Ile HisGlu Glu Phe Pro Arg Glu Leu Glu Ser Ser 2270 2275 2280 Val Ser Phe ProAla Asp Phe Phe Arg Pro Pro Glu Glu Lys Glu 2285 2290 2295 Gly Pro LeuLeu Arg Pro Ala Gly Arg Arg Thr Thr Pro Gln Thr 2300 2305 2310 Thr ArgPro Gly Pro Gly Thr Glu Arg Glu Ala Pro Ile Ser Arg 2315 2320 2325 ArgArg Arg His Pro Asp Asp Ala Gly Gln Phe Ala Val Ala Leu 2330 2335 2340Val Ile Ile Tyr Arg Thr Leu Gly Gln Leu Leu Pro Glu Arg Tyr 2345 23502355 Asp Pro Asp Arg Arg Ser Leu Arg Leu Pro His Arg Pro Ile Ile 23602365 2370 Asn Thr Pro Met Val Ser Thr Leu Val Tyr Ser Glu Gly Ala Pro2375 2380 2385 Leu Pro Arg Pro Leu Glu Arg Pro Val Leu Val Glu Phe AlaLeu 2390 2395 2400 Leu Glu Val Glu Glu Arg Thr Lys Pro Val Cys Val PheTrp Asn 2405 2410 2415 His Ser Leu Ala Val Gly Gly Thr Gly Gly Trp SerAla Arg Gly 2420 2425 2430 Cys Glu Leu Leu Ser Arg Asn Arg Thr His ValAla Cys Gln Cys 2435 2440 2445 Ser His Thr Ala Ser Phe Ala Val Leu MetAsp Ile Ser Arg Arg 2450 2455 2460 Glu Asn Gly Glu Val Leu Pro Leu LysIle Val Thr Tyr Ala Ala 2465 2470 2475 Val Ser Leu Ser Leu Ala Ala LeuLeu Val Ala Phe Val Leu Leu 2480 2485 2490 Ser Leu Val Arg Met Leu ArgSer Asn Leu His Ser Ile His Lys 2495 2500 2505 His Leu Ala Val Ala LeuPhe Leu Ser Gln Leu Val Phe Val Ile 2510 2515 2520 Gly Ile Asn Gln ThrGlu Asn Pro Phe Leu Cys Thr Val Val Ala 2525 2530 2535 Ile Leu Leu HisTyr Ile Tyr Met Ser Thr Phe Ala Trp Thr Leu 2540 2545 2550 Val Glu SerLeu His Val Tyr Arg Met Leu Thr Glu Val Arg Asn 2555 2560 2565 Ile AspThr Gly Pro Met Arg Phe Tyr Tyr Val Val Gly Trp Gly 2570 2575 2580 IlePro Ala Ile Val Thr Gly Leu Ala Val Gly Leu Asp Pro Gln 2585 2590 2595Gly Tyr Gly Asn Pro Asp Phe Cys Trp Leu Ser Leu Gln Asp Thr 2600 26052610 Leu Ile Trp Ser Phe Ala Gly Pro Ile Gly Ala Val Ile Ile Ile 26152620 2625 Asn Thr Val Thr Ser Val Leu Ser Ala Lys Val Ser Cys Gln Arg2630 2635 2640 Lys His His Tyr Tyr Gly Lys Lys Gly Ile Val Ser Leu LeuArg 2645 2650 2655 Thr Ala Phe Leu Leu Leu Leu Leu Ile Ser Ala Thr TrpLeu Leu 2660 2665 2670 Gly Leu Leu Ala Val Asn Arg Asp Ala Leu Ser PheHis Tyr Leu 2675 2680 2685 Phe Ala Ile Phe Ser Gly Leu Gln Gly Pro PheVal Leu Leu Phe 2690 2695 2700 His Cys Val Leu Asn Gln Glu Val Arg LysHis Leu Lys Gly Val 2705 2710 2715 Leu Gly Gly Arg Lys Leu His Leu GluAsp Ser Ala Thr Thr Arg 2720 2725 2730 Ala Thr Leu Leu Thr Arg Ser LeuAsn Cys Asn Thr Thr Phe Gly 2735 2740 2745 Asp Gly Pro Asp Met Leu ArgThr Asp Leu Gly Glu Ser Thr Ala 2750 2755 2760 Ser Leu Asp Ser Ile ValArg Asp Glu Gly Ile Gln Lys Leu Gly 2765 2770 2775 Val Ser Ser Gly LeuVal Arg Gly Ser His Gly Glu Pro Asp Ala 2780 2785 2790 Ser Leu Met ProArg Ser Cys Lys Asp Pro Pro Gly His Asp Ser 2795 2800 2805 Asp Ser AspSer Glu Leu Ser Leu Asp Glu Gln Ser Ser Ser Tyr 2810 2815 2820 Ala SerSer His Ser Ser Asp Ser Glu Asp Asp Gly Val Gly Ala 2825 2830 2835 GluGlu Lys Trp Asp Pro Ala Arg Gly Ala Val His Ser Thr Pro 2840 2845 2850Lys Gly Asp Ala Val Ala Asn His Val Pro Ala Gly Trp Pro Asp 2855 28602865 Gln Ser Leu Ala Glu Ser Asp Ser Glu Asp Pro Ser Gly Lys Pro 28702875 2880 Arg Leu Lys Val Glu Thr Lys Val Ser Val Glu Leu His Arg Glu2885 2890 2895 Glu Gln Gly Ser His Arg Gly Glu Tyr Pro Pro Asp Gln GluSer 2900 2905 2910 Gly Gly Ala Ala Arg Leu Ala Ser Ser Gln Pro Pro GluGln Arg 2915 2920 2925 Lys Gly Ile Leu Lys Asn Lys Val Thr Tyr Pro ProPro Leu Thr 2930 2935 2940 Leu Thr Glu Gln Thr Leu Lys Gly Arg Leu ArgGlu Lys Leu Ala 2945 2950 2955 Asp Cys Glu Gln Ser Pro Thr Ser Ser ArgThr Ser Ser Leu Gly 2960 2965 2970 Ser Gly Gly Pro Asp Cys Ala Ile ThrVal Lys Ser Pro Gly Arg 2975 2980 2985 Glu Pro Gly Arg Asp His Leu AsnGly Val Ala Met Asn Val Arg 2990 2995 3000 Thr Gly Ser Ala Gln Ala AspGly Ser Asp Ser Glu Lys Pro 3005 3010 108 181 PRT Homo Sapien 108 MetVal Asp Val Lys Cys Leu Ser Asp Cys Lys Leu Gln Asn Gln 1 5 10 15 LeuGlu Lys Leu Gly Phe Ser Pro Gly Pro Ile Leu Pro Ser Thr 20 25 30 Arg LysLeu Tyr Glu Lys Lys Leu Val Gln Leu Leu Val Ser Pro 35 40 45 Pro Cys AlaPro Pro Val Met Asn Gly Pro Arg Glu Leu Asp Gly 50 55 60 Ala Gln Asp SerAsp Asp Ser Glu Glu Leu Asn Ile Ile Leu Gln 65 70 75 Gly Asn Ile Ile LeuSer Thr Glu Lys Ser Lys Lys Leu Lys Lys 80 85 90 Trp Pro Glu Ala Ser ThrThr Lys Arg Lys Ala Val Asp Thr Tyr 95 100 105 Cys Leu Asp Tyr Lys ProSer Lys Gly Arg Arg Trp Ala Ala Arg 110 115 120 Ala Pro Ser Thr Arg IleThr Tyr Gly Thr Ile Thr Lys Glu Arg 125 130 135 Asp Tyr Cys Ala Glu AspGln Thr Ile Glu Ser Trp Arg Glu Glu 140 145 150 Gly Phe Pro Val Gly LeuLys Leu Ala Val Leu Gly Ile Phe Ile 155 160 165 Ile Val Val Phe Val TyrLeu Thr Val Glu Asn Lys Ser Leu Phe 170 175 180 Gly 109 620 PRT HomoSapien 109 Met Ser Lys Ser Lys Cys Ser Val Gly Leu Met Ser Ser Val Val 15 10 15 Ala Pro Ala Lys Glu Pro Asn Ala Val Gly Pro Lys Glu Val Glu 2025 30 Leu Ile Leu Val Lys Glu Gln Asn Gly Val Gln Leu Thr Ser Ser 35 4045 Thr Leu Thr Asn Pro Arg Gln Ser Pro Val Glu Ala Gln Asp Arg 50 55 60Glu Thr Trp Gly Lys Lys Ile Asp Phe Leu Leu Ser Val Ile Gly 65 70 75 PheAla Val Asp Leu Ala Asn Val Trp Arg Phe Pro Tyr Leu Cys 80 85 90 Tyr LysAsn Gly Gly Gly Ala Phe Leu Val Pro Tyr Leu Leu Phe 95 100 105 Met ValIle Ala Gly Met Pro Leu Phe Tyr Met Glu Leu Ala Leu 110 115 120 Gly GlnPhe Asn Arg Glu Gly Ala Ala Gly Val Trp Lys Ile Cys 125 130 135 Pro IleLeu Lys Gly Val Gly Phe Thr Val Ile Leu Ile Ser Leu 140 145 150 Tyr ValGly Phe Phe Tyr Asn Val Ile Ile Ala Trp Ala Leu His 155 160 165 Tyr LeuPhe Ser Ser Phe Thr Thr Glu Leu Pro Trp Ile His Cys 170 175 180 Asn AsnSer Trp Asn Ser Pro Asn Cys Ser Asp Ala His Pro Gly 185 190 195 Asp SerSer Gly Asp Ser Ser Gly Leu Asn Asp Thr Phe Gly Thr 200 205 210 Thr ProAla Ala Glu Tyr Phe Glu Arg Gly Val Leu His Leu His 215 220 225 Gln SerHis Gly Ile Asp Asp Leu Gly Pro Pro Arg Trp Gln Leu 230 235 240 Thr AlaCys Leu Val Leu Val Ile Val Leu Leu Tyr Phe Ser Leu 245 250 255 Trp LysGly Val Lys Thr Ser Gly Lys Val Val Trp Ile Thr Ala 260 265 270 Thr MetPro Tyr Val Val Leu Thr Ala Leu Leu Leu Arg Gly Val 275 280 285 Thr LeuPro Gly Ala Ile Asp Gly Ile Arg Ala Tyr Leu Ser Val 290 295 300 Asp PheTyr Arg Leu Cys Glu Ala Ser Val Trp Ile Asp Ala Ala 305 310 315 Thr GlnVal Cys Phe Ser Leu Gly Val Gly Phe Gly Val Leu Ile 320 325 330 Ala PheSer Ser Tyr Asn Lys Phe Thr Asn Asn Cys Tyr Arg Asp 335 340 345 Ala IleVal Thr Thr Ser Ile Asn Ser Leu Thr Ser Phe Ser Ser 350 355 360 Gly PheVal Val Phe Ser Phe Leu Gly Tyr Met Ala Gln Lys His 365 370 375 Ser ValPro Ile Gly Asp Val Ala Lys Asp Gly Pro Gly Leu Ile 380 385 390 Phe IleIle Tyr Pro Glu Ala Ile Ala Thr Leu Pro Leu Ser Ser 395 400 405 Ala TrpAla Val Val Phe Phe Ile Met Leu Leu Thr Leu Gly Ile 410 415 420 Asp SerAla Met Gly Gly Met Glu Ser Val Ile Thr Gly Leu Ile 425 430 435 Asp GluPhe Gln Leu Leu His Arg His Arg Glu Leu Phe Thr Leu 440 445 450 Phe IleVal Leu Ala Thr Phe Leu Leu Ser Leu Phe Cys Val Thr 455 460 465 Asn GlyGly Ile Tyr Val Phe Thr Leu Leu Asp His Phe Ala Ala 470 475 480 Gly ThrSer Ile Leu Phe Gly Val Leu Ile Glu Ala Ile Gly Val 485 490 495 Ala TrpPhe Tyr Gly Val Gly Gln Phe Ser Asp Asp Ile Gln Gln 500 505 510 Met ThrGly Gln Arg Pro Ser Leu Tyr Trp Arg Leu Cys Trp Lys 515 520 525 Leu ValSer Pro Cys Phe Leu Leu Phe Val Val Val Val Ser Ile 530 535 540 Val ThrPhe Arg Pro Pro His Tyr Gly Ala Tyr Ile Phe Pro Asp 545 550 555 Trp AlaAsn Ala Leu Gly Trp Val Ile Ala Thr Ser Ser Met Ala 560 565 570 Met ValPro Ile Tyr Ala Ala Tyr Lys Phe Cys Ser Leu Pro Gly 575 580 585 Ser PheArg Glu Lys Leu Ala Tyr Ala Ile Ala Pro Glu Lys Asp 590 595 600 Arg GluLeu Val Asp Arg Gly Glu Val Arg Gln Phe Thr Leu Arg 605 610 615 His TrpLeu Lys Val 620 110 442 PRT Homo Sapien 110 Met Gly Leu Ala Met Glu HisGly Gly Ser Tyr Ala Arg Ala Gly 1 5 10 15 Gly Ser Ser Arg Gly Cys TrpTyr Tyr Leu Arg Tyr Phe Phe Leu 20 25 30 Phe Val Ser Leu Ile Gln Phe LeuIle Ile Leu Gly Leu Val Leu 35 40 45 Phe Met Val Tyr Gly Asn Val His ValSer Thr Glu Ser Asn Leu 50 55 60 Gln Ala Thr Glu Arg Arg Ala Glu Gly LeuTyr Ser Gln Leu Leu 65 70 75 Gly Leu Thr Ala Ser Gln Ser Asn Leu Thr LysGlu Leu Asn Phe 80 85 90 Thr Thr Arg Ala Lys Asp Ala Ile Met Gln Met TrpLeu Asn Ala 95 100 105 Arg Arg Asp Leu Asp Arg Ile Asn Ala Ser Phe ArgGln Cys Gln 110 115 120 Gly Asp Arg Val Ile Tyr Thr Asn Asn Gln Arg TyrMet Ala Ala 125 130 135 Ile Ile Leu Ser Glu Lys Gln Cys Arg Asp Gln PheLys Asp Met 140 145 150 Asn Lys Ser Cys Asp Ala Leu Leu Phe Met Leu AsnGln Lys Val 155 160 165 Lys Thr Leu Glu Val Glu Ile Ala Lys Glu Lys ThrIle Cys Thr 170 175 180 Lys Asp Lys Glu Ser Val Leu Leu Asn Lys Arg ValAla Glu Glu 185 190 195 Gln Leu Val Glu Cys Val Lys Thr Arg Glu Leu GlnHis Gln Glu 200 205 210 Arg Gln Leu Ala Lys Glu Gln Leu Gln Lys Val GlnAla Leu Cys 215 220 225 Leu Pro Leu Asp Lys Asp Lys Phe Glu Met Asp LeuArg Asn Leu 230 235 240 Trp Arg Asp Ser Ile Ile Pro Arg Ser Leu Asp AsnLeu Gly Tyr 245 250 255 Asn Leu Tyr His Pro Leu Gly Ser Glu Leu Ala SerIle Arg Arg 260 265 270 Ala Cys Asp His Met Pro Ser Leu Met Ser Ser LysVal Glu Glu 275 280 285 Leu Ala Arg Ser Leu Arg Ala Asp Ile Glu Arg ValAla Arg Glu 290 295 300 Asn Ser Asp Leu Gln Arg Gln Lys Leu Glu Ala GlnGln Gly Leu 305 310 315 Arg Ala Ser Gln Glu Ala Lys Gln Lys Val Glu LysGlu Ala Gln 320 325 330 Ala Arg Glu Ala Lys Leu Gln Ala Glu Cys Ser ArgGln Thr Gln 335 340 345 Leu Ala Leu Glu Glu Lys Ala Val Leu Arg Lys GluArg Asp Asn 350 355 360 Leu Ala Lys Glu Leu Glu Glu Lys Lys Arg Glu AlaGlu Gln Leu 365 370 375 Arg Met Glu Leu Ala Ile Arg Asn Ser Ala Leu AspThr Cys Ile 380 385 390 Lys Thr Lys Ser Gln Pro Met Met Pro Val Ser ArgPro Met Gly 395 400 405 Pro Val Pro Asn Pro Gln Pro Ile Asp Pro Ala SerLeu Glu Glu 410 415 420 Phe Lys Arg Lys Ile Leu Glu Ser Gln Arg Pro ProAla Gly Ile 425 430 435 Pro Val Ala Pro Ser Ser Gly 440 111 170 PRT HomoSapien 111 Met Met Ala Gly Met Lys Ile Gln Leu Val Cys Met Leu Leu Leu 15 10 15 Ala Phe Ser Ser Trp Ser Leu Cys Ser Asp Ser Glu Glu Glu Met 2025 30 Lys Ala Leu Glu Ala Asp Phe Leu Thr Asn Met His Thr Ser Lys 35 4045 Ile Ser Lys Ala His Val Pro Ser Trp Lys Met Thr Leu Leu Asn 50 55 60Val Cys Ser Leu Val Asn Asn Leu Asn Ser Pro Ala Glu Glu Thr 65 70 75 GlyGlu Val His Glu Glu Glu Leu Val Ala Arg Arg Lys Leu Pro 80 85 90 Thr AlaLeu Asp Gly Phe Ser Leu Glu Ala Met Leu Thr Ile Tyr 95 100 105 Gln LeuHis Lys Ile Cys His Ser Arg Ala Phe Gln His Trp Glu 110 115 120 Leu IleGln Glu Asp Ile Leu Asp Thr Gly Asn Asp Lys Asn Gly 125 130 135 Lys GluGlu Val Ile Lys Arg Lys Ile Pro Tyr Ile Leu Lys Arg 140 145 150 Gln LeuTyr Glu Asn Lys Pro Arg Arg Pro Tyr Ile Leu Lys Arg 155 160 165 Asp SerTyr Tyr Tyr 170 112 502 PRT Homo Sapien 112 Met Leu Leu Arg Ser Ala GlyLys Leu Asn Val Gly Thr Lys Lys 1 5 10 15 Glu Asp Gly Glu Ser Thr AlaPro Thr Pro Arg Pro Lys Val Leu 20 25 30 Arg Cys Lys Cys His His His CysPro Glu Asp Ser Val Asn Asn 35 40 45 Ile Cys Ser Thr Asp Gly Tyr Cys PheThr Met Ile Glu Glu Asp 50 55 60 Asp Ser Gly Leu Pro Val Val Thr Ser GlyCys Leu Gly Leu Glu 65 70 75 Gly Ser Asp Phe Gln Cys Arg Asp Thr Pro IlePro His Gln Arg 80 85 90 Arg Ser Ile Glu Cys Cys Thr Glu Arg Asn Glu CysAsn Lys Asp 95 100 105 Leu His Pro Thr Leu Pro Pro Leu Lys Asn Arg AspPhe Val Asp 110 115 120 Gly Pro Ile His His Arg Ala Leu Leu Ile Ser ValThr Val Cys 125 130 135 Ser Leu Leu Leu Val Leu Ile Ile Leu Phe Cys TyrPhe Arg Tyr 140 145 150 Lys Arg Gln Glu Thr Arg Pro Arg Tyr Ser Ile GlyLeu Glu Gln 155 160 165 Asp Glu Thr Tyr Ile Pro Pro Gly Glu Ser Leu ArgAsp Leu Ile 170 175 180 Glu Gln Ser Gln Ser Ser Gly Ser Gly Ser Gly LeuPro Leu Leu 185 190 195 Val Gln Arg Thr Ile Ala Lys Gln Ile Gln Met ValLys Gln Ile 200 205 210 Gly Lys Gly Arg Tyr Gly Glu Val Trp Met Gly LysTrp Arg Gly 215 220 225 Glu Lys Val Ala Val Lys Val Phe Phe Thr Thr GluGlu Ala Ser 230 235 240 Trp Phe Arg Glu Thr Glu Ile Tyr Gln Thr Val LeuMet Arg His 245 250 255 Glu Asn Ile Leu Gly Phe Ile Ala Ala Asp Ile LysGly Thr Gly 260 265 270 Ser Trp Thr Gln Leu Tyr Leu Ile Thr Asp Tyr HisGlu Asn Gly 275 280 285 Ser Leu Tyr Asp Tyr Leu Lys Ser Thr Thr Leu AspAla Lys Ser 290 295 300 Met Leu Lys Leu Ala Tyr Ser Ser Val Ser Gly LeuCys His Leu 305 310 315 His Thr Glu Ile Phe Ser Thr Gln Gly Lys Pro AlaIle Ala His 320 325 330 Arg Asp Leu Lys Ser Lys Asn Ile Leu Val Lys LysAsn Gly Thr 335 340 345 Cys Cys Ile Ala Asp Leu Gly Leu Ala Val Lys PheIle Ser Asp 350 355 360 Thr Asn Glu Val Asp Ile Pro Pro Asn Thr Arg ValGly Thr Lys 365 370 375 Arg Tyr Met Pro Pro Glu Val Leu Asp Glu Ser LeuAsn Arg Asn 380 385 390 His Phe Gln Ser Tyr Ile Met Ala Asp Met Tyr SerPhe Gly Leu 395 400 405 Ile Leu Trp Glu Val Ala Arg Arg Cys Val Ser GlyGly Ile Val 410 415 420 Glu Glu Tyr Gln Leu Pro Tyr His Asp Leu Val ProSer Asp Pro 425 430 435 Ser Tyr Glu Asp Met Arg Glu Ile Val Cys Ile LysLys Leu Arg 440 445 450 Pro Ser Phe Pro Asn Arg Trp Ser Ser Asp Glu CysLeu Arg Gln 455 460 465 Met Gly Lys Leu Met Thr Glu Cys Trp Ala His AsnPro Ala Ser 470 475 480 Arg Leu Thr Ala Leu Arg Val Lys Lys Thr Leu AlaLys Met Ser 485 490 495 Glu Ser Gln Asp Ile Lys Leu 500 113 2403 DNAHomo Sapien 113 ttgaagtgca ttgctgcagc tggtagcatg agtggtggcc accacctgca50 gctggctgcc ctctggccct ggctgctgat ggctaccctg caggcaggct 100 ttggacgcacaggactggta ctggcagcag cggtggagtc tgaaagatca 150 gcagaacaga aagctgttatcagagtgatc cccttgaaaa tggaccccac 200 aggaaaactg aatctcactt tggaaggtgtgtttgctggt gttgctgaaa 250 taactccagc agaaggaaaa ttaatgcagt cccacccgctgtacctgtgc 300 aatgccagtg atgacgacaa tctggagcct ggattcatca gcatcgtcaa350 gctggagagt cctcgacggg ccccccaccc ctgcctgtca ctggctagca 400aggctcggat ggcgggtgag cgaggagcca gtgctgtcct ctttgacatc 450 actgaggatcgagctgctgc tgagcagctg cagcagccgc tggggctgac 500 ctggccagtg gtgttgatctggggtaatga cgctgagaag ctgatggagt 550 ttgtgtacaa gaaccaaaag gcccatgtgaggattgagct gaaggagccc 600 ccggcctggc cagattatga tgtgtggatc ctaatgacagtggtgggcac 650 catctttgtg atcatcctgg cttcggtgct gcgcatccgg tgccgccccc700 gccacagcag gccggatccg cttcagcaga gaacagcctg ggccatcagc 750cagctggcca ccaggaggta ccaggccagc tgcaggcagg cccggggtga 800 gtggccagactcagggagca gctgcagctc agcccctgtg tgtgccatct 850 gtctggagga gttctctgaggggcaggagc tacgggtcat ttcctgcctc 900 catgagttcc atcgtaactg tgtggacccctggttacatc agcatcggac 950 ttgccccctc tgcatgttca acatcacaga gggagattcattttcccagt 1000 ccctgggacc ctctcgatct taccaagaac caggtcgaag actccacctc1050 attcgccagc atcccggcca tgcccactac cacctccctg ctgcctacct 1100gttgggccct tcccggagtg cagtggctcg gcccccacga cctggtccct 1150 tcctgccatcccaggagcca ggcatgggcc ctcggcatca ccgcttcccc 1200 agagctacac atccccgggctccaggagag cagcagcgcc tggcaggagc 1250 ccagcacccc tatgcacaag gctggggactgagccacctc caatccacct 1300 cacagcaccc tgctgcttgc ccagtgcccc tacgccgggccaggccccct 1350 gacagcagtg gatctggaga aagctattgc acagaacgca gtgggtacct1400 ggcagatggg ccagccagtg actccagctc agggccctgt catggctctt 1450ccagtgactc tgtggtcaac tgcacggaca tcagcctaca gggggtccat 1500 ggcagcagttctactttctg cagctcccta agcagtgact ttgaccccct 1550 agtgtactgc agccctaaaggggatcccca gcgagtggac atgcagccta 1600 gtgtgacctc tcggcctcgt tccttggactcggtggtgcc cacaggggaa 1650 acccaggttt ccagccatgt ccactaccac cgccaccggcaccaccacta 1700 caaaaagcgg ttccagtggc atggcaggaa gcctggccca gaaaccggag1750 tcccccagtc caggcctcct attcctcgga cacagcccca gccagagcca 1800ccttctcctg atcagcaagt caccagatcc aactcagcag ccccttcggg 1850 gcggctctctaacccacagt gccccagggc cctccctgag ccagcccctg 1900 gcccagttga cgcctccagcatctgcccca gtaccagcag tctgttcaac 1950 ttgcaaaaat ccagcctctc tgcccgacacccacagagga aaaggcgggg 2000 gggtccctcc gagcccaccc ctggctctcg gccccaggatgcaactgtgc 2050 acccagcttg ccagattttt ccccattaca cccccagtgt ggcatatcct2100 tggtccccag aggcacaccc cttgatctgt ggacctccag gcctggacaa 2150gaggctgcta ccagaaaccc caggcccctg ttactcaaat tcacagccag 2200 tgtggttgtgcctgactcct cgccagcccc tggaaccaca tccacctggg 2250 gaggggcctt ctgaatggagttctgacacc gcagagggca ggccatgccc 2300 ttatccgcac tgccaggtgc tgtcggcccagcctggctca gaggaggaac 2350 tcgaggagct gtgtgaacag gctgtgtgag atgttcaggcctagctccaa 2400 cca 2403 114 783 PRT Homo Sapien 114 Met Ser Gly Gly HisHis Leu Gln Leu Ala Ala Leu Trp Pro Trp 1 5 10 15 Leu Leu Met Ala ThrLeu Gln Ala Gly Phe Gly Arg Thr Gly Leu 20 25 30 Val Leu Ala Ala Ala ValGlu Ser Glu Arg Ser Ala Glu Gln Lys 35 40 45 Ala Val Ile Arg Val Ile ProLeu Lys Met Asp Pro Thr Gly Lys 50 55 60 Leu Asn Leu Thr Leu Glu Gly ValPhe Ala Gly Val Ala Glu Ile 65 70 75 Thr Pro Ala Glu Gly Lys Leu Met GlnSer His Pro Leu Tyr Leu 80 85 90 Cys Asn Ala Ser Asp Asp Asp Asn Leu GluPro Gly Phe Ile Ser 95 100 105 Ile Val Lys Leu Glu Ser Pro Arg Arg AlaPro His Pro Cys Leu 110 115 120 Ser Leu Ala Ser Lys Ala Arg Met Ala GlyGlu Arg Gly Ala Ser 125 130 135 Ala Val Leu Phe Asp Ile Thr Glu Asp ArgAla Ala Ala Glu Gln 140 145 150 Leu Gln Gln Pro Leu Gly Leu Thr Trp ProVal Val Leu Ile Trp 155 160 165 Gly Asn Asp Ala Glu Lys Leu Met Glu PheVal Tyr Lys Asn Gln 170 175 180 Lys Ala His Val Arg Ile Glu Leu Lys GluPro Pro Ala Trp Pro 185 190 195 Asp Tyr Asp Val Trp Ile Leu Met Thr ValVal Gly Thr Ile Phe 200 205 210 Val Ile Ile Leu Ala Ser Val Leu Arg IleArg Cys Arg Pro Arg 215 220 225 His Ser Arg Pro Asp Pro Leu Gln Gln ArgThr Ala Trp Ala Ile 230 235 240 Ser Gln Leu Ala Thr Arg Arg Tyr Gln AlaSer Cys Arg Gln Ala 245 250 255 Arg Gly Glu Trp Pro Asp Ser Gly Ser SerCys Ser Ser Ala Pro 260 265 270 Val Cys Ala Ile Cys Leu Glu Glu Phe SerGlu Gly Gln Glu Leu 275 280 285 Arg Val Ile Ser Cys Leu His Glu Phe HisArg Asn Cys Val Asp 290 295 300 Pro Trp Leu His Gln His Arg Thr Cys ProLeu Cys Met Phe Asn 305 310 315 Ile Thr Glu Gly Asp Ser Phe Ser Gln SerLeu Gly Pro Ser Arg 320 325 330 Ser Tyr Gln Glu Pro Gly Arg Arg Leu HisLeu Ile Arg Gln His 335 340 345 Pro Gly His Ala His Tyr His Leu Pro AlaAla Tyr Leu Leu Gly 350 355 360 Pro Ser Arg Ser Ala Val Ala Arg Pro ProArg Pro Gly Pro Phe 365 370 375 Leu Pro Ser Gln Glu Pro Gly Met Gly ProArg His His Arg Phe 380 385 390 Pro Arg Ala Thr His Pro Arg Ala Pro GlyGlu Gln Gln Arg Leu 395 400 405 Ala Gly Ala Gln His Pro Tyr Ala Gln GlyTrp Gly Leu Ser His 410 415 420 Leu Gln Ser Thr Ser Gln His Pro Ala AlaCys Pro Val Pro Leu 425 430 435 Arg Arg Ala Arg Pro Pro Asp Ser Ser GlySer Gly Glu Ser Tyr 440 445 450 Cys Thr Glu Arg Ser Gly Tyr Leu Ala AspGly Pro Ala Ser Asp 455 460 465 Ser Ser Ser Gly Pro Cys His Gly Ser SerSer Asp Ser Val Val 470 475 480 Asn Cys Thr Asp Ile Ser Leu Gln Gly ValHis Gly Ser Ser Ser 485 490 495 Thr Phe Cys Ser Ser Leu Ser Ser Asp PheAsp Pro Leu Val Tyr 500 505 510 Cys Ser Pro Lys Gly Asp Pro Gln Arg ValAsp Met Gln Pro Ser 515 520 525 Val Thr Ser Arg Pro Arg Ser Leu Asp SerVal Val Pro Thr Gly 530 535 540 Glu Thr Gln Val Ser Ser His Val His TyrHis Arg His Arg His 545 550 555 His His Tyr Lys Lys Arg Phe Gln Trp HisGly Arg Lys Pro Gly 560 565 570 Pro Glu Thr Gly Val Pro Gln Ser Arg ProPro Ile Pro Arg Thr 575 580 585 Gln Pro Gln Pro Glu Pro Pro Ser Pro AspGln Gln Val Thr Arg 590 595 600 Ser Asn Ser Ala Ala Pro Ser Gly Arg LeuSer Asn Pro Gln Cys 605 610 615 Pro Arg Ala Leu Pro Glu Pro Ala Pro GlyPro Val Asp Ala Ser 620 625 630 Ser Ile Cys Pro Ser Thr Ser Ser Leu PheAsn Leu Gln Lys Ser 635 640 645 Ser Leu Ser Ala Arg His Pro Gln Arg LysArg Arg Gly Gly Pro 650 655 660 Ser Glu Pro Thr Pro Gly Ser Arg Pro GlnAsp Ala Thr Val His 665 670 675 Pro Ala Cys Gln Ile Phe Pro His Tyr ThrPro Ser Val Ala Tyr 680 685 690 Pro Trp Ser Pro Glu Ala His Pro Leu IleCys Gly Pro Pro Gly 695 700 705 Leu Asp Lys Arg Leu Leu Pro Glu Thr ProGly Pro Cys Tyr Ser 710 715 720 Asn Ser Gln Pro Val Trp Leu Cys Leu ThrPro Arg Gln Pro Leu 725 730 735 Glu Pro His Pro Pro Gly Glu Gly Pro SerGlu Trp Ser Ser Asp 740 745 750 Thr Ala Glu Gly Arg Pro Cys Pro Tyr ProHis Cys Gln Val Leu 755 760 765 Ser Ala Gln Pro Gly Ser Glu Glu Glu LeuGlu Glu Leu Cys Glu 770 775 780 Gln Ala Val 115 2407 DNA Homo Sapien 115ccctttgaag tgcattgctg cagctggtag catgagtggt ggccaccagc 50 tgcagctggctgccctctgg ccctggctgc tgatggctac cctgcaggca 100 ggctttggac gcacaggactggtactggca gcagcggtgg agtctgaaag 150 atcagcagaa cagaaagctg ttatcagagtgatccccttg aaaatggacc 200 ccacaggaaa actgaatctc actttggaag gtgtgtttgctggtgttgct 250 gaaataactc cagcagaagg aaaattaatg cagtcccacc cgctgtacct300 gtgcaatgcc agtgatgacg acaatctgga gcctggattc atcagcatcg 350tcaagctgga gagtcctcga cgggcccccc gcccctgcct gtcactggct 400 agcaaggctcggatggcggg tgagcgagga gccagtgctg tcctctttga 450 catcactgag gatcgagctgctgctgagca gctgcagcag ccgctggggc 500 tgacctggcc agtggtgttg atctggggtaatgacgctga gaagctgatg 550 gagtttgtgt acaagaacca aaaggcccat gtgaggattgagctgaagga 600 gcccccggcc tggccagatt atgatgtgtg gatcctaatg acagtggtgg650 gcaccatctt tgtgatcatc ctggcttcgg tgctgcgcat ccagtgccgc 700ccccgccaca gcaggccgga tccgcttcag cagagaacag cctgggccat 750 cagccagctggccaccagga ggtaccaggc cagctgcagg caggcccggg 800 gtgagtggcc agactcagggagcagctgca gctcagcccc tgtgtgtgcc 850 atctgtctgg aggagttctc tgaggggcaggagctacggg tcatttcctg 900 cctccatgag ttccatcgta actgtgtgga cccctggttacatcagcatc 950 ggacttgccc cctctgcatg ttcaacatca cagagggaga ttcattttcc1000 cagtccctgg gaccctctcg atcttaccaa gaaccaggtc gaagactcca 1050cctcattcgc cagcatcccg gccatgccca ctaccacctc cctgctgcct 1100 acctgttgggcccttcccgg agtgcagtgg ctcggccccc acgacctggt 1150 cccttcctgc catcccaggagccaggcatg ggccctcggc atcaccgctt 1200 ccccagagct gcacatcccc gggctccaggagagcagcag cgcctggcag 1250 gagcccagca cccctatgca caaggctggg gactgagccacctccaatcc 1300 acctcacagc accctgctgc ttgcccagtg cccctacgcc gggccaggcc1350 ccctgacagc agtggatctg gagaaagcta ttgcacagaa cgcagtgggt 1400acctggcaga tgggccagcc agtgactcca gctcagggcc ctgtcatggc 1450 tcttccagtgactctgtggt caactgcacg gacatcagcc tacagggggt 1500 ccatggcagc agttctactttctgcagctc cctaagcagt gactttgacc 1550 ccctagtgta ctgcagccct aaaggggatccccagcgagt ggacatgcag 1600 cctagtgtga cctctcggcc tcgttccttg gactcggtggtgcccacagg 1650 ggaaacccag gtttccagcc atgtccacta ccaccgccac cggcaccacc1700 actacaaaaa gcggttccag tggcatggca ggaagcctgg cccagaaacc 1750ggagtccccc agtccaggcc tcctattcct cggacacagc cccagccaga 1800 gccaccttctcctgatcagc aagtcaccag atccaactca gcagcccctt 1850 cggggcggct ctctaacccacagtgcccca gggccctccc tgagccagcc 1900 cctggcccag ttgacgcctc cagcatctgccccagtacca gcagtctgtt 1950 caacttgcaa aaatccagcc tctctgcccg acacccacagaggaaaaggc 2000 gggggggtcc ctccgagccc acccctggct ctcggcccca ggatgcaact2050 gtgcacccag cttgccagat ttttccccat tacaccccca gtgtggcata 2100tccttggtcc ccagaggcac accccttgat ctgtggacct ccaggcctgg 2150 acaagaggctgctaccagaa accccaggcc cctgttactc aaattcacag 2200 ccagtgtggt tgtgcctgactcctcgccag cccctggaac cacatccacc 2250 tggggagggg ccttctgaat ggagttctgacaccgcagag ggcaggccat 2300 gcccttgtcc gcactgccag gtgctgtcgg cccagcctggctcagaggag 2350 gaactcgagg agctgtgtga acaggctgtg tgagatgttc aggcctagct2400 ccaacca 2407 116 783 PRT Homo Sapien 116 Met Ser Gly Gly His GlnLeu Gln Leu Ala Ala Leu Trp Pro Trp 1 5 10 15 Leu Leu Met Ala Thr LeuGln Ala Gly Phe Gly Arg Thr Gly Leu 20 25 30 Val Leu Ala Ala Ala Val GluSer Glu Arg Ser Ala Glu Gln Lys 35 40 45 Ala Val Ile Arg Val Ile Pro LeuLys Met Asp Pro Thr Gly Lys 50 55 60 Leu Asn Leu Thr Leu Glu Gly Val PheAla Gly Val Ala Glu Ile 65 70 75 Thr Pro Ala Glu Gly Lys Leu Met Gln SerHis Pro Leu Tyr Leu 80 85 90 Cys Asn Ala Ser Asp Asp Asp Asn Leu Glu ProGly Phe Ile Ser 95 100 105 Ile Val Lys Leu Glu Ser Pro Arg Arg Ala ProArg Pro Cys Leu 110 115 120 Ser Leu Ala Ser Lys Ala Arg Met Ala Gly GluArg Gly Ala Ser 125 130 135 Ala Val Leu Phe Asp Ile Thr Glu Asp Arg AlaAla Ala Glu Gln 140 145 150 Leu Gln Gln Pro Leu Gly Leu Thr Trp Pro ValVal Leu Ile Trp 155 160 165 Gly Asn Asp Ala Glu Lys Leu Met Glu Phe ValTyr Lys Asn Gln 170 175 180 Lys Ala His Val Arg Ile Glu Leu Lys Glu ProPro Ala Trp Pro 185 190 195 Asp Tyr Asp Val Trp Ile Leu Met Thr Val ValGly Thr Ile Phe 200 205 210 Val Ile Ile Leu Ala Ser Val Leu Arg Ile GlnCys Arg Pro Arg 215 220 225 His Ser Arg Pro Asp Pro Leu Gln Gln Arg ThrAla Trp Ala Ile 230 235 240 Ser Gln Leu Ala Thr Arg Arg Tyr Gln Ala SerCys Arg Gln Ala 245 250 255 Arg Gly Glu Trp Pro Asp Ser Gly Ser Ser CysSer Ser Ala Pro 260 265 270 Val Cys Ala Ile Cys Leu Glu Glu Phe Ser GluGly Gln Glu Leu 275 280 285 Arg Val Ile Ser Cys Leu His Glu Phe His ArgAsn Cys Val Asp 290 295 300 Pro Trp Leu His Gln His Arg Thr Cys Pro LeuCys Met Phe Asn 305 310 315 Ile Thr Glu Gly Asp Ser Phe Ser Gln Ser LeuGly Pro Ser Arg 320 325 330 Ser Tyr Gln Glu Pro Gly Arg Arg Leu His LeuIle Arg Gln His 335 340 345 Pro Gly His Ala His Tyr His Leu Pro Ala AlaTyr Leu Leu Gly 350 355 360 Pro Ser Arg Ser Ala Val Ala Arg Pro Pro ArgPro Gly Pro Phe 365 370 375 Leu Pro Ser Gln Glu Pro Gly Met Gly Pro ArgHis His Arg Phe 380 385 390 Pro Arg Ala Ala His Pro Arg Ala Pro Gly GluGln Gln Arg Leu 395 400 405 Ala Gly Ala Gln His Pro Tyr Ala Gln Gly TrpGly Leu Ser His 410 415 420 Leu Gln Ser Thr Ser Gln His Pro Ala Ala CysPro Val Pro Leu 425 430 435 Arg Arg Ala Arg Pro Pro Asp Ser Ser Gly SerGly Glu Ser Tyr 440 445 450 Cys Thr Glu Arg Ser Gly Tyr Leu Ala Asp GlyPro Ala Ser Asp 455 460 465 Ser Ser Ser Gly Pro Cys His Gly Ser Ser SerAsp Ser Val Val 470 475 480 Asn Cys Thr Asp Ile Ser Leu Gln Gly Val HisGly Ser Ser Ser 485 490 495 Thr Phe Cys Ser Ser Leu Ser Ser Asp Phe AspPro Leu Val Tyr 500 505 510 Cys Ser Pro Lys Gly Asp Pro Gln Arg Val AspMet Gln Pro Ser 515 520 525 Val Thr Ser Arg Pro Arg Ser Leu Asp Ser ValVal Pro Thr Gly 530 535 540 Glu Thr Gln Val Ser Ser His Val His Tyr HisArg His Arg His 545 550 555 His His Tyr Lys Lys Arg Phe Gln Trp His GlyArg Lys Pro Gly 560 565 570 Pro Glu Thr Gly Val Pro Gln Ser Arg Pro ProIle Pro Arg Thr 575 580 585 Gln Pro Gln Pro Glu Pro Pro Ser Pro Asp GlnGln Val Thr Arg 590 595 600 Ser Asn Ser Ala Ala Pro Ser Gly Arg Leu SerAsn Pro Gln Cys 605 610 615 Pro Arg Ala Leu Pro Glu Pro Ala Pro Gly ProVal Asp Ala Ser 620 625 630 Ser Ile Cys Pro Ser Thr Ser Ser Leu Phe AsnLeu Gln Lys Ser 635 640 645 Ser Leu Ser Ala Arg His Pro Gln Arg Lys ArgArg Gly Gly Pro 650 655 660 Ser Glu Pro Thr Pro Gly Ser Arg Pro Gln AspAla Thr Val His 665 670 675 Pro Ala Cys Gln Ile Phe Pro His Tyr Thr ProSer Val Ala Tyr 680 685 690 Pro Trp Ser Pro Glu Ala His Pro Leu Ile CysGly Pro Pro Gly 695 700 705 Leu Asp Lys Arg Leu Leu Pro Glu Thr Pro GlyPro Cys Tyr Ser 710 715 720 Asn Ser Gln Pro Val Trp Leu Cys Leu Thr ProArg Gln Pro Leu 725 730 735 Glu Pro His Pro Pro Gly Glu Gly Pro Ser GluTrp Ser Ser Asp 740 745 750 Thr Ala Glu Gly Arg Pro Cys Pro Cys Pro HisCys Gln Val Leu 755 760 765 Ser Ala Gln Pro Gly Ser Glu Glu Glu Leu GluGlu Leu Cys Glu 770 775 780 Gln Ala Val 117 2403 DNA Homo Sapien 117ttgaagtgca ttgctgcagc tggtagcatg agtggtggcc accacctgca 50 gctggctgccctctggccct ggctgctgat ggctaccctg caggcaggct 100 ttggacgcac aggactggtactggcagcag cggtggagtc tgaaagatca 150 gcagaacaga aagctgttat cagagtgatccccttgaaaa tggaccccac 200 aggaaaactg aatctcactt tggaaggtgt gtttgctggtgttgctgaaa 250 taactccagc agaaggaaaa ttaatgcagt cccacccgct gtacctgtgc300 aatgccagtg atgacgacaa tctggagcct ggattcatca gcatcgtcaa 350gctggagagt cctcgacggg ccccccaccc ctgcctgtca ctggctagca 400 aggctcggatggcgggtgag cgaggagcca gtgctgtcct ctttgacatc 450 actgaggatc gagctgctgctgagcagctg cagcagccgc tggggctgac 500 ctggccagtg gtgttgatct ggggtaatgacgctgagaag ctgatggagt 550 ttgtgtacaa gaaccaaaag gcccatgtga ggattgagctgaaggagccc 600 ccggcctggc cagattatga tgtgtggatc ctaatgacag tggtgggcac650 catctttgtg atcatcctgg cttcggtgct gcgcatccgg tgccgccccc 700gccacagcag gccggatccg cttcagcaga gaacagcctg ggccatcagc 750 cagctggccaccaggaggta ccaggccagc tgcaggcagg cccggggtga 800 gtggccagac tcagggagcagctgcagctc agcccctgtg tgtgccatct 850 gtctggagga gttctctgag gggcaggagctacgggtcat ttcctgcctc 900 catgagttcc atcgtaactg tgtggacccc tggttacatcagcatcggac 950 ttgccccctc tgcatgttca acatcacaga gggagattca ttttcccagt1000 ccctgggacc ctctcgatct taccaagaac caggtcgaag actccacctc 1050attcgccagc atcccggcca tgcccactac cacctccctg ctgcctacct 1100 gttgggcccttcccggagtg cagtggctcg gcccccacga cctggtccct 1150 tcctgccatc ccaggagccaggcatgggcc ctcggcatca ccgcttcccc 1200 agagctgcac atccccgggc tccaggagagcagcagcgcc tggcaggagc 1250 ccagcacccc tatgcacaag gctggggaat gagccacctccaatccacct 1300 cacagcaccc tgctgcttgc ccagtgcccc tacgccgggc caggccccct1350 gacagcagtg gatctggaga aagctattgc acagaacgca gtgggtacct 1400ggcagatggg ccagccagtg actccagctc agggccctgt catggctctt 1450 ccagtgactctgtggtcaac tgcacggaca tcagcctaca gggggtccat 1500 ggcagcagtt ctactttctgcagctcccta agcagtgact ttgaccccct 1550 agtgtactgc agccctaaag gggatccccagcgagtggac atgcagccta 1600 gtgtgacctc tcggcctcgt tccttggact cggtggtgcccacaggggaa 1650 acccaggttt ccagccatgt ccactaccac cgccaccggc accaccacta1700 caaaaagcgg ttccagtggc atggcaggaa gcctggccca gaaaccggag 1750tcccccagtc caggcctcct attcctcgga cacagcccca gccagagcca 1800 ccttctcctgatcagcaagt caccagatcc aactcagcag ccccttcggg 1850 gcggctctct aacccacagtgccccagggc cctccctgag ccagcccctg 1900 gcccagttga cgcctccagc atctgccccagtaccagcag tctgttcaac 1950 ttgcaaaaat ccagcctctc tgcccgacac ccacagaggaaaaggcgggg 2000 gggtccctcc gagcccaccc ctggctctcg gccccaggat gcaactgtgc2050 acccagcttg ccagattttt ccccattaca cccccagtgt ggcatatcct 2100tggtccccag aggcacaccc cttgatctgt ggacctccag gcctggacaa 2150 gaggctgctaccagaaaccc caggcccctg ttactcaaat tcacagccag 2200 tgtggttgtg cctgactcctcgccagcccc tggaaccaca tccacctggg 2250 gaggggcctt ctgaatggag ttctgacaccgcagagggca ggccatgccc 2300 ttatccgcac tgccaggtgc tgtcggccca gcctggctcagaggaggaac 2350 tcgaggagct gtgtgaacag gctgtgtgag atgttcaggc ctagctccaa2400 cca 2403 118 783 PRT Homo Sapien 118 Met Ser Gly Gly His His LeuGln Leu Ala Ala Leu Trp Pro Trp 1 5 10 15 Leu Leu Met Ala Thr Leu GlnAla Gly Phe Gly Arg Thr Gly Leu 20 25 30 Val Leu Ala Ala Ala Val Glu SerGlu Arg Ser Ala Glu Gln Lys 35 40 45 Ala Val Ile Arg Val Ile Pro Leu LysMet Asp Pro Thr Gly Lys 50 55 60 Leu Asn Leu Thr Leu Glu Gly Val Phe AlaGly Val Ala Glu Ile 65 70 75 Thr Pro Ala Glu Gly Lys Leu Met Gln Ser HisPro Leu Tyr Leu 80 85 90 Cys Asn Ala Ser Asp Asp Asp Asn Leu Glu Pro GlyPhe Ile Ser 95 100 105 Ile Val Lys Leu Glu Ser Pro Arg Arg Ala Pro HisPro Cys Leu 110 115 120 Ser Leu Ala Ser Lys Ala Arg Met Ala Gly Glu ArgGly Ala Ser 125 130 135 Ala Val Leu Phe Asp Ile Thr Glu Asp Arg Ala AlaAla Glu Gln 140 145 150 Leu Gln Gln Pro Leu Gly Leu Thr Trp Pro Val ValLeu Ile Trp 155 160 165 Gly Asn Asp Ala Glu Lys Leu Met Glu Phe Val TyrLys Asn Gln 170 175 180 Lys Ala His Val Arg Ile Glu Leu Lys Glu Pro ProAla Trp Pro 185 190 195 Asp Tyr Asp Val Trp Ile Leu Met Thr Val Val GlyThr Ile Phe 200 205 210 Val Ile Ile Leu Ala Ser Val Leu Arg Ile Arg CysArg Pro Arg 215 220 225 His Ser Arg Pro Asp Pro Leu Gln Gln Arg Thr AlaTrp Ala Ile 230 235 240 Ser Gln Leu Ala Thr Arg Arg Tyr Gln Ala Ser CysArg Gln Ala 245 250 255 Arg Gly Glu Trp Pro Asp Ser Gly Ser Ser Cys SerSer Ala Pro 260 265 270 Val Cys Ala Ile Cys Leu Glu Glu Phe Ser Glu GlyGln Glu Leu 275 280 285 Arg Val Ile Ser Cys Leu His Glu Phe His Arg AsnCys Val Asp 290 295 300 Pro Trp Leu His Gln His Arg Thr Cys Pro Leu CysMet Phe Asn 305 310 315 Ile Thr Glu Gly Asp Ser Phe Ser Gln Ser Leu GlyPro Ser Arg 320 325 330 Ser Tyr Gln Glu Pro Gly Arg Arg Leu His Leu IleArg Gln His 335 340 345 Pro Gly His Ala His Tyr His Leu Pro Ala Ala TyrLeu Leu Gly 350 355 360 Pro Ser Arg Ser Ala Val Ala Arg Pro Pro Arg ProGly Pro Phe 365 370 375 Leu Pro Ser Gln Glu Pro Gly Met Gly Pro Arg HisHis Arg Phe 380 385 390 Pro Arg Ala Ala His Pro Arg Ala Pro Gly Glu GlnGln Arg Leu 395 400 405 Ala Gly Ala Gln His Pro Tyr Ala Gln Gly Trp GlyMet Ser His 410 415 420 Leu Gln Ser Thr Ser Gln His Pro Ala Ala Cys ProVal Pro Leu 425 430 435 Arg Arg Ala Arg Pro Pro Asp Ser Ser Gly Ser GlyGlu Ser Tyr 440 445 450 Cys Thr Glu Arg Ser Gly Tyr Leu Ala Asp Gly ProAla Ser Asp 455 460 465 Ser Ser Ser Gly Pro Cys His Gly Ser Ser Ser AspSer Val Val 470 475 480 Asn Cys Thr Asp Ile Ser Leu Gln Gly Val His GlySer Ser Ser 485 490 495 Thr Phe Cys Ser Ser Leu Ser Ser Asp Phe Asp ProLeu Val Tyr 500 505 510 Cys Ser Pro Lys Gly Asp Pro Gln Arg Val Asp MetGln Pro Ser 515 520 525 Val Thr Ser Arg Pro Arg Ser Leu Asp Ser Val ValPro Thr Gly 530 535 540 Glu Thr Gln Val Ser Ser His Val His Tyr His ArgHis Arg His 545 550 555 His His Tyr Lys Lys Arg Phe Gln Trp His Gly ArgLys Pro Gly 560 565 570 Pro Glu Thr Gly Val Pro Gln Ser Arg Pro Pro IlePro Arg Thr 575 580 585 Gln Pro Gln Pro Glu Pro Pro Ser Pro Asp Gln GlnVal Thr Arg 590 595 600 Ser Asn Ser Ala Ala Pro Ser Gly Arg Leu Ser AsnPro Gln Cys 605 610 615 Pro Arg Ala Leu Pro Glu Pro Ala Pro Gly Pro ValAsp Ala Ser 620 625 630 Ser Ile Cys Pro Ser Thr Ser Ser Leu Phe Asn LeuGln Lys Ser 635 640 645 Ser Leu Ser Ala Arg His Pro Gln Arg Lys Arg ArgGly Gly Pro 650 655 660 Ser Glu Pro Thr Pro Gly Ser Arg Pro Gln Asp AlaThr Val His 665 670 675 Pro Ala Cys Gln Ile Phe Pro His Tyr Thr Pro SerVal Ala Tyr 680 685 690 Pro Trp Ser Pro Glu Ala His Pro Leu Ile Cys GlyPro Pro Gly 695 700 705 Leu Asp Lys Arg Leu Leu Pro Glu Thr Pro Gly ProCys Tyr Ser 710 715 720 Asn Ser Gln Pro Val Trp Leu Cys Leu Thr Pro ArgGln Pro Leu 725 730 735 Glu Pro His Pro Pro Gly Glu Gly Pro Ser Glu TrpSer Ser Asp 740 745 750 Thr Ala Glu Gly Arg Pro Cys Pro Tyr Pro His CysGln Val Leu 755 760 765 Ser Ala Gln Pro Gly Ser Glu Glu Glu Leu Glu GluLeu Cys Glu 770 775 780 Gln Ala Val 119 4839 DNA Homo Sapien 119ggaaagctag cggcagaggc tcagccccgg cggcagcgcg cgccccgctg 50 ccagcccattttccggacgc cacccgcggg cactgccgac gcccccgggg 100 ctgccgaggg gaggccgggggggcgcagcg gagcgcggtc ccgcgcactg 150 agccccgcgg cgccccggga acttggcggcgacccgagcc cggcgagccg 200 gggcgcgcct cccccgccgc gcgcctcctg catgcggggccccagctccg 250 ggcgccggcc ggagcccccc ccggccgccc ccgagccccc cgcgccccgc300 gccgcgccgc cgcgccgtcc atgcaccgct tgatgggggt caacagcacc 350gccgccgccg ccgccgggca gcccaatgtc tcctgcacgt gcaactgcaa 400 acgctctttgttccagagca tggagatcac ggagctggag tttgttcaga 450 tcatcatcat cgtggtggtgatgatggtga tggtggtggt gatcacgtgc 500 ctgctgagcc actacaagct gtctgcacggtccttcatca gccggcacag 550 ccaggggcgg aggagagaag atgccctgtc ctcagaaggatgcctgtggc 600 cctcggagag cacagtgtca ggcaacggaa tcccagagcc gcaggtctac650 gccccgcctc ggcccaccga ccgcctggcc gtgccgccct tcgcccagcg 700ggagcgcttc caccgcttcc agcccaccta tccgtacctg cagcacgaga 750 tcgacctgccacccaccatc tcgctgtcag acggggagga gcccccaccc 800 taccagggcc cctgcaccctccagcttcgg gaccccgagc agcagctgga 850 actgaaccgg gagtcggtgc gcgcacccccaaacagaacc atcttcgaca 900 gtgacctgat ggatagtgcc aggctgggcg gcccctgcccccccagcagt 950 aactcgggca tcagcgccac gtgctacggc agcggcgggc gcatggaggg1000 gccgccgccc acctacagcg aggtcatcgg ccactacccg gggtcctcct 1050tccagcacca gcagagcagt gggccgccct ccttgctgga ggggacccgg 1100 ctccaccacacacacatcgc gcccctagag agcgcagcca tctggagcaa 1150 agagaaggat aaacagaaaggacaccctct ctagggtccc caggggggcc 1200 gggctggggc tgcgtaggtg aaaaggcagaacactccgcg cttcttagaa 1250 gaggagtgag aggaaggcgg ggggcgcagc aacgcatcgtgtggccctcc 1300 cctcccacct ccctgtgtat aaatatttac atgtgatgtc tggtctgaat1350 gcacaagcta agagagcttg caaaaaaaaa aagaaaaaag aaaaaaaaaa 1400accacgtttc tttgttgagc tgtgtcttga aggcaaaaga aaaaaaattt 1450 ctacagtagtctttcttgtt tctagttgag ctgcgtgcgt gaatgcttat 1500 tttcttttgt ttatgataatttcacttaac tttaaagaca tatttgcaca 1550 aaacctttgt ttaaagatct gcaatattatatatataaat atatataaga 1600 taagagaaac tgtatgtgcg agggcaggag tatttttgtattagaagagg 1650 cctattaaaa aaaaaagttg ttttctgaac tagaagagga aaaaaatggc1700 aatttttgag tgccaagtca gaaagtgtgt attaccttgt aaagaaaaaa 1750attacaaagc aggggtttag agttatttat ataaatgttg agattttgca 1800 ctattttttaatataaatat gtcagtgctt gcttgatgga aacttctctt 1850 gtgtctgttg agactttaagggagaaatgt cggaatttca gagtcgcctg 1900 acggcagagg gtgagccccc gtggagtctgcagagaggcc ttggccagga 1950 gcggcgggct ttcccgaggg gccactgtcc ctgcagagtggatgcttctg 2000 cctagtgaca ggttatcacc acgttatata ttccctaccg aaggagacac2050 cttttccccc ctgacccaga acagccttta aatcacaagc aaaataggaa 2100agttaaccac ggaggcaccg agttccaggt agtggttttg cctttcccaa 2150 aaatgaaaataaactgttac cgaaggaatt agtttttcct cttctttttt 2200 ccaactgtga aggtccccgtggggtggagc atggtgcccc tcacaagccg 2250 cagcggctgg tgcccgggct accagggacatgccagaggg ctcgatgact 2300 tgtctctgca gggcgctttg gtggttgttc agctggctaaaggttcaccg 2350 gtgaaggcag gtgcggtaac tgccgcactg gaccctagga agccccaggt2400 attcgcaatc tgacctcctc ctgtctgttt cccttcacgg atcaattctc 2450acttaagagg ccaataaaca acccaacatg aaaaggtgac aagcctgggt 2500 ttctcccaggataggtgaaa gggttaaaat gagtaaagca gttgagcaaa 2550 caccaacccg agcttcgggcgcagaattct tcaccttctc ttcccctttc 2600 catctccttt ccccgcggaa acaacgcttcccttctggtg tgtctgttga 2650 tctgtgtttt catttacatc tctcttagac tccgctcttgttctccaggt 2700 tttcaccaga tagatttggg gttggcggga cctgctggtg acgtgcaggt2750 gaaggacagg aaggggcatg tgagcgtaaa tagaggtgac cagaggagag 2800catgaggggt ggggctttgg gacccaccgg ggccagtggc tggagcttga 2850 cgtctttcctccccatgggg gtgggagggc ccccagctgg aagagcagac 2900 tcccagctgc taccccctcccttcccatgg gagtggcttt ccattttggg 2950 cagaatgctg actagtagac taacataaaagatataaaag gcaataacta 3000 ttgtttgtga gcaacttttt tataacttcc aaaacaaaaacctgagcaca 3050 gttttgaagt tctagccact cgagctcatg catgtgaaac gtgtgcttta3100 cgaaggtggc agctgacaga cgtgggctct gcatgccgcc agcctagtag 3150aaagttctcg ttcattggca acagcagaac ctgcctctcc gtgaagtcgt 3200 cagcctaaaatttgtttctc tcttgaagag gattctttga aaaggtcctg 3250 cagagaaatc agtacaggttatcccgaaag gtacaaggac gcacttgtaa 3300 agatgattaa aacgtatctt tcctttatgtgacgcgtctc tagtgcctta 3350 ctgaagaagc agtgacactc ccgtcgctcg gtgaggacgttcccggacag 3400 tgcctcactc acctgggact ggtatcccct cccagggtcc accaagggct3450 cctgcttttc agacacccca tcatcctcgc gcgtcctcac cctgtctcta 3500ccagggaggt gcctagcttg gtgaggttac tcctgctcct ccaacctttt 3550 tttgccaaggtttgtacacg actcccatct aggctgaaaa cctagaagtg 3600 gaccttgtgt gtgtgcatggtgtcagccca aagccaggct gagacagtcc 3650 tcatatcctc ttgagccaaa ctgtttgggtctcgttgctt catggtatgg 3700 tctggatttg tgggaatggc tttgcgtgag aaaggggaggagagtggttg 3750 ctgccctcag ccggcttgag gacagagcct gtccctctca tgacaactca3800 gtgttgaagc ccagtgtcct cagcttcatg tccagtggat ggcagaagtt 3850catggggtag tggcctctca aaggctgggc gcatcccaag acagccagca 3900 ggttgtctctggaaacgacc agagttaagc tctcggcttc tctgctgagg 3950 gtgcaccctt tcctctagatggtagttgtc acgttatctt tgaaaactct 4000 tggactgctc ctgaggaggc cctcttttccagtaggaagt tagatggggg 4050 ttctcagaag tggctgattg gaaggggaca agcttcgtttcaggggtctg 4100 ccgttccatc ctggttcaga gaaggccgag cgtggctttc tctagccttg4150 tcactgtctc cctgcctgtc aatcaccacc tttcctccag aggaggaaaa 4200ttatctcccc tgcaaagccc ggttctacac agatttcaca aattgtgcta 4250 agaaccgtccgtgttctcag aaagcccagt gtttttgcaa agaatgaaaa 4300 gggaccccat atgtagcaaaaatcagggct gggggagagc cgggttcatt 4350 ccctgtcctc attggtcgtc cctatgaattgtacgtttca gagaaatttt 4400 ttttcctatg tgcaacacga agcttccaga accataaaatatcccgtcga 4450 taaggaaaga aaatgtcgtt gttgttgttt ttctggaaac tgcttgaaat4500 cttgctgtac tatagagctc agaaggacac agcccgtcct cccctgcctg 4550cctgattcca tggctgttgt gctgattcca atgctttcac gttggttcct 4600 ggcgtgggaactgctctcct ttgcagcccc atttcccaag ctctgttcaa 4650 gttaaactta tgtaagctttccgtggcatg cggggcgcgc acccacgtcc 4700 ccgctgcgta agactctgta tttggatgccaatccacagg cctgaagaaa 4750 ctgcttgttg tgtatcagta atcattagtg gcaatgatgacattctgaaa 4800 agctgcaata cttatacaat aaattttaca attctttgg 4839 120 287PRT Homo Sapien 120 Met His Arg Leu Met Gly Val Asn Ser Thr Ala Ala AlaAla Ala 1 5 10 15 Gly Gln Pro Asn Val Ser Cys Thr Cys Asn Cys Lys ArgSer Leu 20 25 30 Phe Gln Ser Met Glu Ile Thr Glu Leu Glu Phe Val Gln IleIle 35 40 45 Ile Ile Val Val Val Met Met Val Met Val Val Val Ile Thr Cys50 55 60 Leu Leu Ser His Tyr Lys Leu Ser Ala Arg Ser Phe Ile Ser Arg 6570 75 His Ser Gln Gly Arg Arg Arg Glu Asp Ala Leu Ser Ser Glu Gly 80 8590 Cys Leu Trp Pro Ser Glu Ser Thr Val Ser Gly Asn Gly Ile Pro 95 100105 Glu Pro Gln Val Tyr Ala Pro Pro Arg Pro Thr Asp Arg Leu Ala 110 115120 Val Pro Pro Phe Ala Gln Arg Glu Arg Phe His Arg Phe Gln Pro 125 130135 Thr Tyr Pro Tyr Leu Gln His Glu Ile Asp Leu Pro Pro Thr Ile 140 145150 Ser Leu Ser Asp Gly Glu Glu Pro Pro Pro Tyr Gln Gly Pro Cys 155 160165 Thr Leu Gln Leu Arg Asp Pro Glu Gln Gln Leu Glu Leu Asn Arg 170 175180 Glu Ser Val Arg Ala Pro Pro Asn Arg Thr Ile Phe Asp Ser Asp 185 190195 Leu Met Asp Ser Ala Arg Leu Gly Gly Pro Cys Pro Pro Ser Ser 200 205210 Asn Ser Gly Ile Ser Ala Thr Cys Tyr Gly Ser Gly Gly Arg Met 215 220225 Glu Gly Pro Pro Pro Thr Tyr Ser Glu Val Ile Gly His Tyr Pro 230 235240 Gly Ser Ser Phe Gln His Gln Gln Ser Ser Gly Pro Pro Ser Leu 245 250255 Leu Glu Gly Thr Arg Leu His His Thr His Ile Ala Pro Leu Glu 260 265270 Ser Ala Ala Ile Trp Ser Lys Glu Lys Asp Lys Gln Lys Gly His 275 280285 Pro Leu

What is claimed is:
 1. An isolated polypeptide comprising the amino acidsequence of SEQ ID NO:93.
 2. A chimeric polypeptide comprising thepolypeptide of claim 1 fused to a heterologous polypeptide.
 3. Thechimeric polypeptide of claim 2, wherein said heterologous polypeptideis an epitope tag sequence or an Fc region of an immunoglobulin.